0 med chem, chapter 25, 75 pages, post.pptpsbeauchamp/pdf/499_med_chem_topic_25.pdf · 31/5/2017...

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What is histamine? - Looks simple. Made from aminoacid histidine.

N

N

N

H

H

H

histamineN

N

N

H

H

H

histidine

O OH

How is it made – Handout.

What does it do? – Four different receptors known now. All part of G protein-coupled family.

H1 – immune response that causes hives, makes blood vessels leaky

pKa's = 5.7, 9.8 pKa's = 1.9, 6.0, 9.3

© Oxford University Press, 20131

H2 – stimulates stomach acid secretion, H3 – found in CNS and can inhibit release of other neurotransmitters, H4 - found in bone marrow and white blood cells and regulates neutrophil

release from bone marrow. It is also expressed in the colon, liver, lung, small intestine, spleen, testes, thymus, tonsils, and trachea

Hives also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. They may also burn or sting. Often the patches of rash move around.

Hives often occur following an infection or as a result of an allergic reaction such as to medication, insect bites, food, psychological stress, cold temperature, or vibrations. In half of cases the cause remains unknown. Risk factors include having conditions such as hay fever or asthma. Diagnosis is typically based on the appearance. Patch testing may be useful to determine the allergy. Prevention is by avoiding whatever it is that causes the condition Typically they last a few days and do not leave any long-lasting skin changescondition. Typically they last a few days and do not leave any long lasting skin changes. Fewer than 5% of cases last for more than six weeks. The condition frequently recurs.

Treatment is typically with antihistamines such as diphenhydramine and ranitidine. In severe cases, corticosteroids or leukotriene inhibitors may also be used. Antihistamines that block the histamine H1 receptors are the first line of therapy.

About 20% of people are affected. Cases of short


p pduration occur equally in males and females while cases of long duration are more common in females. Cases of short duration are more common among children while cases of long duration are more common among those who are middle aged. Hives have been described at least since the time of Hippocrates. The term urticaria is from the Latin urtica meaning "nettle“.

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Peptic ulcer disease (PUD), is a break in the lining of the stomach, first part of the small intestine, or occasionally the lower esophagus. An ulcer in the stomach is known as a gastric ulcer while that in the first part of the intestines is known as a duodenal ulcer. Common symptoms upper abdominal pain that improves with eating. Other symptoms include belching, vomiting, weight loss, or poor appetite. About a third of older people have no symptoms. Complications may include bleeding, (15% of people) with an ulcer perforation, and blockage of the stomach.

Common causes include the bacteria Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs). Other less common causes include tobacco smoking, stress due to serious illness, Crohn disease and liver cirrhosis, among others. H. pylori can be diagnosed by testing the blood for antibodies or a biopsy of the stomach.

Diet does not play an important role in either causing or preventing ulcers Treatment includes stopping smokingDiet does not play an important role in either causing or preventing ulcers. Treatment includes stopping smoking, stopping NSAIDs, stopping alcohol, and medications to decrease stomach acid. The medication used to decrease acid is usually either a proton pump inhibitor (PPI) or an H2 blocker . Ulcers due to H. pylori are treated with a combination of medications such as amoxicillin, clarithromycin, and a PPI.

Peptic ulcers are present in around 4% of the population. They newly began in around 87.4 million persons worldwide in 2015. About 10% of people develop a peptic ulcer at some point in their life. They resulted in 267,500 deaths in 2015 down from 327,000 deaths in 1990.


In the early 1960s only one class of antihistamine was known (H1 now)

First generation antihistamines

Clinically, H1-antihistamines are used to treat allergic reactions and mast cell-related disorders. Sedation is a common side effect of H1-antihistamines that readily cross h bl d b i b i f h d h

ON

diphenhydramine(Benadryl)

the blood–brain barrier; some of these drugs, such as diphenhydramine and doxylamine, are therefore used to treat insomnia. H1-antihistamines can also reduce inflammation.


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N

N

N

O

M i

Second generation antihistamines Mepyramine crosses the blood–brain barrier to a much lower degree than the first-generation antihistamines. Their main benefit is they primarily affect peripheral histamine receptors (as opposed to the CNS) and therefore are less sedating. However, high doses can still induce the central nervous system drowsiness. The reason

Mepyramine for their peripheral selectivity is that most of these compounds are zwitterionic at physiological pH (around pH 7.4). As such, they are very polar, meaning that they do not easily cross the blood–brain barrier and act mainly outside the central nervous system.

O O H

Possible synthesis


N

N

N

O

NH2

NN

O

O

HH

OC

O

H

N

NO

H

Cl

Mepyramine

O

S

ketotifen

Second generation antihistamines Ketotifen is a noncompetitive H1-antihistamine and mast cell stabilizer. It is most commonly sold as a salt with fumaric acid, ketotifen fumarate, and is available in two forms. In its ophthalmic form, it is used to treat allergic conjunctivitis, or the itchy red eyes caused by allergies. In its oral form, it is used to prevent asthma attacks. Ketotifen

N

relieves and prevents eye itchiness and/or irritation associated with most seasonal allergies. It starts working within minutes after administering the drops. The mean elimination half life is 12 hours.


It was known that histamine stimulated stomach acid, but none of the known antihistamines inhibited acid secretion.

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Ulcers•Localised erosions of the mucous membranes of the stomach and duodenum•Potentially fatal if untreated•Caused by stress, infection (H. Pylori), smoking and drugs (NSAIDS)•Agrevated by gastric acid (HCl) in the stomach•Estimated 1 out of 10 people will have one sometime in their life

ANTI-ULCER AGENTS - HISTAMINE ANTAGONISTS

Estimated 1 out of 10 people will have one sometime in their life

Therapy of ulcers

•Old days: antacids, bland diet (crackers, milk), surgery on stomach

•New days:•Lower the levels of gastric acid

hi i i d


a. histamine antagonists and b. proton pump inhibitors

•Antibacterial agents vs. H. Pylori•Herbal remedies

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oesophagus

Histamine

Acetylcholine

Gastrin

M3

H

Parietal cells and gastric acid release

+

+

+

A

Stomach

Cck2H2

Parietal Cells

Stomach

cAMP

++

+

+

+ -H

HCl

Cl


AntrumPyloricSphincter

Duodenum Proton pump

Receptors

Ion channel

Notes•Release of gastric acid is promoted by acetylcholine, gastrin and histamine

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O

O3SO

CO2CO2

sulfonated tyrosine

HN

GlyO

ProTrp

LeuGlu

GluGlu

GluGlu

AlaNH

O

GlyTrp

MetAsp

PheNH3

CO2 O2C CO2 CO2

gastrin - peptide hormone(made by G cells)

modif ied Glu

H3C

O

O

H2C

CN

CH3

CH3

CH

H3N

N H


H3C O CH2

CH3

acetyl cholineN

histamine


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Biosynthesis of histamine from the amino acid histidine (with vitamine B6)

N

H O

OH

H

-2O3PO

PLP - vitamine B6(aldehyde version)

N

HO O

N

N

H

histidine(pKa's = 1.8, 6.1, 9.3)

H

H

BH

N

H

H

N

H

CO2HO

H

NH

N

BH

BB

(aldehyde version) H

N

H

H

N

C

NH

N

OO

H

N

H

H

NNH

NO

HH

BH

N

H

H

NNH

N

BHA similar process occurs with many other amino acids, including synthesis of neurotransmitters serotonin and dopamine (which forms epinephrine and norepinephrine). Glutamate can react in a similar manner

PLP - vitamine B6(imine version)

CO

O

BB


H

N

H

H

N

H

O

H

NH

N

BH

N

H O

H

H N

H

NH

N

histamine

manner.

Histamine is released when cells are damaged. It increases the permeabililty of small blood vessels and allows white blood cells into that area to defend against infection. Allergic reactions and irritation are common side effects.

PLP - vitamine B6(aldehyde version)

B

Histamine - Properties•A chemical messenger released by cells •Acts as a local hormone

Notes•Two possible tautomers•pKa for the -NH2 group = 9.80.•% ionisation at pH 7.4 = 99.6•pKa for the imidazole ring = 5.74•Imidazole ring is slightly ionized at blood pH

Hplasma pH = 7.4

Percent conjugate acid and conjugate base

H N

H

N

NH

H

pKa1 = 5.7

H N

H

N

NH

H

pKa2 = 9.8

H N

H

N

N

pH - pKa = log[B:]

[HB+]

7.4 - 5.7 = 1.7 = log

= 101.7 = 50 / 1 = 98% / 2%

pH - pKa = log

7.4 - 9.8 = -2.4 = log

= 10-2.4 = 1 / 250 = 0.4% / 99.6%

What could make thepKa go higher or lower?The conjugate acid ispositive and theconjugate base is neutral.

H

Two tautomer possibilities

[B:]

[HB+]

[B:]

[HB+]

[B:]

[HB+][B:]

[HB+][B:]

[HB+]


H3NN

N

H H3NN

N

H

H H3NN

N

H

H H3NN

N

HB H

Bis closer to the side chain

N

N

H

H

How does the pKa of imidazole compare to pKa1 of histamine?(higher, lower or similar)?

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Histamine Actions

Histamine is released by cell damage

Stimulates dilation of blood vessels with increased permeabilityStimulates dilation of blood vessels with increased permeability

White blood cells escape blood vessels and access area of tissue damage


Histamine is also released by allergies, asthma, hay fever and insect bites

BUT

White blood cells combat infection

13

Commonly used to treat symptoms such as inflammation & itching

Classical antihistamines

N

MeO NMe2O

NMe2

•But no effect on gastric acid release •Casts doubt on histamine receptors being present on parietal cells•Histamine may promote gastric acid release indirectly•SK&F propose two types of histamine receptor (H1 and H2)(SKF = Smith, Kline & French)

N

Mepyramine Diphenhydramine Benadryl


(SKF Smith, Kline & French)•H1 - responsible for classical actions of histamine•H2 - proposed as the receptor on the parietal cells in the stomach•Claim that H2 receptors are unaffected by classical antihistamines•Implies classical antihistamines are H1 specific

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•No known H2 antagonist at the time - no lead compound•SK&F decide to use histamine itself as the lead compound•Aim is to alter an agonist into an antagonist•Compare development of propranolol (-blocker) from adrenaline•Need to know SAR requirements for H2 agonists•Analogues tested by their ability to promote gastric acid release•Does not prove existence of H2 receptor

Histamine used as the lead compound

H3NN

N

H

histamine = lead compound

S-epinephrine (adrenoline) was used as a lead compound for labetalol. SKF proposed to follow a similar strategy to find an antagonist for histamine stomach acid secretion.

N

HO

HOMe

OH

epinephrine(adrenoline)

N

HO

OHO

H2N

H H

changes to adrenergic antagonist

changes to adrenergic antagonist


Epinephrine is a nonselective agonist of a variety of adrenergic receptors,including the major subtypes 1, 2, 1, 2, and 3, triggering a number of metabolic changes. Binding to -adrenergic receptors inhibits insulin secretion by the pancreas, stimulates glycogenolysis in the liver and muscle, and stimulates glycolysis and inhibits insulin-mediated glycogenesis in muscle. adrenergic receptor binding triggers glucagon secretion in the pancreas, increased adrenocorticotropic hormone (ACTH) secretion by the pituitary gland, and increased lipolysis by adipose tissue. Together, these effects lead to increased blood glucose and fatty acids, providing substrates for energy production within cells throughout the body.

Labetalol is used to lower blood pressure and heart rate. It was the first drug created that combined both alpha- and beta- adrenergic receptor blocking properties. It was postulated that weak blocking of both alpha- and beta- receptors could work together to decrease blood pressure. Labetalol was not found to cross the blood-brain-barrier.

Two nitrogen atoms are required for H1 agonist activity - hivesAll three nitrogen atoms are required for H2 agonist activity – stomach acid

SAR for H1 and H2 agonists

NH3

HNN

NH3

HNN


H1 Receptor H2 Receptor

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•Add extra functional groups to find extra binding interactions with the binding site•Extra binding interactions may result in a different mode of binding resulting in a different induced fit for the receptor

•Different induced fit may fail to activate the receptor•As a result, analogue binds but fails to activate the receptor•Antagonist is likely to bind more strongly than an agonist

Strategies for converting agonists to antagonists

NH3

HN

N

Histamine

Receptor (Inactive)

NH3

HN

N

Induced Fit - Receptor 'Switched on'

HN

Extra Functionality

© Oxford University Press, 201317Different induced fit

Receptor (Inactive)

NH2

HN

N

Functionality

NH2

HN

N

Receptor (Inactive)

Examples - extra hydrophobic groups? Over 200 compounds were made without anyantagonist using hydrophobic groups.

Strategies for converting agonists to antagonists

N

N

N

H

H

H

H N

N

N

H

R2

R1

N

N

N

H

R2

R1

H

R4

histamine R3possible changes

But 2 of them made SKF believe there were 2 different receptors for “hives” vs. “stomach acid”.

NN

NH3

H NN

NH3

H

12

3

4 5

2

13

4 5

The 2 methylhistamine The 4-methylhistamine was


The 2-methylhistaminewas an H1 agonist (hives).

The 4 methylhistamine wasan H2 agonist (stomach acid).

The thought was steric hindrance might restrain rotations of the aminoethyl side chain.

NN

H

C CNH3

NN

NH3

H

2

13

4 5

HH

H

H

H

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N-Guanylhistamine

Guanidinium group

•Next step was to try adding extra hydrophilic groups instead•Aim was to search for extra polar binding regions

N

N NH

HH

H

Biological properties

•Partial agonist - promotes HCl release but less strongly than histamine (possible reason?)

•Prevents histamine from fully promoting the release of HCl

•SK&F suggested that N guanylhistamine was binding to the proposed H receptor

NN N

H H

H


•SK&F suggested that Nguanylhistamine was binding to the proposed H2 receptor, resulting in weak activation

• While present, Nguanylhistamine blocks histamine from binding

19

•The guanidine group is basic and ionized•Different tautomers are possible•The positive charge can be delocalized over 3 resonance structures•There are many possible shapes

N-Guanylhistamine - Structure and chemical properties

HN

HNN

NH2

NH2

HN

HNN

NH2

NH2

HN

HNN

NH2

NH2

HN

HNN

NH2

H2N


The positive charge is more diffuse and can be further away from the imidazole ring. SKF also tried several derivatives without the imidazole ring, but none showed antagonist activity. A decision was made that the imidazole ring was necessary for receptor recognition. This proved to be a very costly mistake when a few years later competitors, Glaxo(ranitidine/Zantac) and Yamanouchi (famotidine/Pepcid) made even more active H2 antihistamines without the imidazole ring that made even more money.

N H2N

20

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Binding theory for agonists and antagonistsPossible binding regions

N

antagonistbinding region

•Three binding regions are proposed for the H2 receptor - an imidazole binding region (H bonds) and two polar binding regions

N

N

NH3

H N

N

NH

H

NH2

NH2agonistbinding region

imidazole ringbinding region imidazole ring

binding region

versus

agonistbinding region


•Two binding modes are proposed - one for agonists and one for antagonists•The imidazole binding region is common to both binding modes•Proposed that one of the polar binding regions is accessed by agonists and the other byantagonists. The antagonist polar region is further from the imidazole binding region

21

Binding of histamine

N

N


imidazole ringbinding region N


•Histamine has a short chain•Charged -nitrogen can only reach the polar agonist region

NH

NH2

N

NH3

H

imidazole ringbinding region

No interaction as an antagonist Strong interaction as an agonist


•The antagonist binding region is out of range•Histamine can only bind as an agonist, so acts as a pure agonist

22

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Binding of N-guanylhistamine

N

N



N

N

H

NH2


•Positive charge on the structure is more diffuse and further out•Allows N-guanylhistamine to bind in two different modes

NH

NH

H2N NH2

NH

HNH2


binding as an weak agonistreceptor weakly activated

binding as an antagonistreceptor not activated


•Structure binds as an agonist in one mode and as an antagonist in the other mode, making it a partial agonist

23

Chelation binding theory - The proposal

HNN

X N

NH H

H

H

O

stronginteraction C C

bondlength (pm)

C F

C N

C O

C H 106A

154A

147 A143 A134 A

SK&F proposed that the guanidine moiety interacts with a carboxylate ion in the antagonist binding region by means of two H-bonds and an ionic interaction

The evidence

S NH2HN NH2

HN NH2

O ReceptorX = -NH, -S C S 181 A


Structures A, B and B’ are all partial agonists, but structure A has greater antagonist properties. What does that suggest?

24

HNN NH2

HNN S

Me

HNN

N NH2

MeA B B'

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Chelation binding theory

Binding modes for analogues

S N

H

strongeri i

H

k

H

HNN

S N

NH H

H

O

O Receptor

interaction

HNN

N N

X

H

O

O Receptor

weakerinteraction

X = -Me, -SMe

Positive charge is localized further out leading to better interactions with the antagonist binding region

Only one H-bond is possible with the antagonist binding region. Charge is also directed away from the carboxylate ion -


weaker antagonist property.

The chelation binding theory was eventually disproved, but it served a purpose in explaining results and pushing the project forward on rational grounds

N

N

SH

NH2

NH2N

N

SH

NH

NH2

less potent

Another possibility considered was altering the side chain to make it more conformationally rigid. How could it be made more rigid?

However, when the more rigid analog was found to be less potent it was felt that side chain flexibility was necessary. Could have tried different ring sizes (but we don’t know all of the compounds). Probably wanted minimal changes possible.


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Aim: To push the polar guanidine group further out and to increase the interaction with the antagonist binding region.

Chain extension strategy

Results

NH H+

3C b id

+

3C bridgeN

H H

HNN

N NH

HH

+ +

guanidinium ion

3C bridge

+

isothiourea

3C bridge

HNN

S NH

H

Partial agonist. Antagonist activity increases

Partial agonistAntagonist activity decreases!


•Antagonist activity of the extended guanidine analogue increases as expected.•Isothiourea analogue might have been expected to have increased antagonist activity since the charge is further out, but it didn’t.

27

N

HN N

N

HN N

N

X

X

N

H H

H

H H

H

+

+

+ +

many, manypossibilities

There are many possible substituents, shapes and polar interactions. Remember, decisions are made by how much acid gets secreted in a rats stomach based on pH reading .

N

HN N

N

HN N

N X X NH

H

H

H

H

H

O

+

+

+

+

possibilities

OR O P

O

O O S

O

O

p


OR

X = -SCH3, -CH3

RN N

X

H H

H RN N

X

H H

H

R O R O

possibilities

R

NH3

X = -NH2

RN N

NH2

H H

H RN N

NH2

H H

H RN N

NH2

H H

H

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Proposed binding for 3C extension analogues

Chain extension strategy

Stronger

HNN

N N

NH H

H

HH

+

+ +

3C bridge

+

+

3C bridge

HNN

S N

NH H

H

H

Weaker

Is there a different form of hydrogen bonding taking place?

Receptor

Strongerinteraction

O O

Receptor

Weaker interaction

O O

Compare 2C bridged analogues.


HNN

X N

NH H

H

H

O

O

Receptor

Stronger interaction

X = NH, S

Antagonistbinding region

Agonist

Imidazole ringbinding region

Summarize effects

HN

N

HN

NH2

NH2HN

N

HN

NH

NH2

Good binding as an antagonist Partial binding as an agonist

binding region NH2

HNN

N NH

X

H H

Partial agonists with good antagonist activity (X= Me or SMe)

X


HNN

N NH

O O

H H

ReceptorX=NH2,SMe,Me


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HNN

N NH

X

H H

Partial agonists with good antagonist activity (X= Me or SMe)

HNN

N NH

X

H H

St i t ti

S

NH2

HN

NH2

O O

ReceptorX=NH2,SMe,Me



Agonistbinding region

Agonistbinding region

Poor binding as an antagonist Good binding as an antagonist

Emphasis now switches to the types of binding interactions at the polar binding regions

HN

N

NH2 HN

N

X

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Distinguishing between the polar binding regions

1 StrategyReplace the ionic guanidine group with a neutral H-bonding group

2 RationaleMay allow a distinction to be made between the two polar binding regionsMay allow a distinction to be made between the two polar binding regions.Ionic bonding is known to be crucial for the agonist binding regionIt may not be crucial for the antagonist binding region

3 MethodReplace the basic guanidine moiety with a neutral thiourea group

ThioureaSK&F 91581 HN


No agonist activityVery weak antagonist

SK&F 91581 HN

N

HN NH2

S

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Similarities - Planarity, geometry, size, polarity, H-bonding abilityDifferences - Thiourea is neutral while guanidine is basic and ionised

Comparison between the thiourea and guanidine groups

Distinguishing between the polar binding regions

R

HN NH2

Se- withdrawing

Thiourea

Neutral

R 2C eak antagonist

R

HN NH2

NH2

Guanidine

Basic


Conclusions -•Agonist polar region involves ionic and H-bonding interactions•Antagonist polar region may not require ionic interactions. H-bonding may be sufficient

33

R = 2C = weak antagonistR = 3C = better antagonist

StrategyExtend the carbon bridge to 4 carbons (another CH2 in the side chain)Pushes thiourea group further outMay increase the interaction with the antagonist binding region

Chain extension (again), and addition of N-methyl group

H

ResultsDiscovery of burimamide

Properties of burimamide

•100 times more active as an antagonist compared to N-guanylhistamine•No antagonist activity at H1 receptors•Activity still too low for oral use

N N

SChain extension

N

N

CH3

HH

What does methyl do? 1. more hydrophobic?2. desolvation effect

(less water to slough off)


Conclusions •Chain extension leads to a pure antagonist with good activity•Chain extension allows a better overlap of the thiourea group with the antagonist binding region

•N-methyl effect (hydrophobic pocket or desolvation?)•Establishes the existence of H2 receptors

y

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The imidazole ringStructures – more complicated than appears at first look

N

H

N

H

N

H

B

N

•Imidazole ring can exist as two tautomers (I) and (II) as well as an intermediate with tworesonance forms (III)

•Which of these is preferred? •Which nitrogen atom in III is more positive? (Depends on what “R” is)

RN

B H

RN

H

RN

H

RN

H

I III II


Which nitrogen atom in III is more positive? (Depends on what R is)

35

The imidazole ring basicity

N

N

H

NH3

H

N

N

H

Percent ionization of imidazole ring at physiological pH 7.4

H N N

S

N

N

CH3

HH

H

e- withdrawing e- donating

Conclusions

•The imidazole ring of histamine is not ionized when it interacts with the imidazole binding region

•The ionized form of burimamide is unlikely to bind well

H HHistamine (pKa 5.74)

Ionization 2% of imidazole ringBurimamide (pKa = 7.25)

Ionization 40% of imidazole ringImidazole (pKa 6.80)

Ionization 25%(H is reference group)

HH


•Decreasing the basicity and ionization of the imidazole ring in burimamide closer to that of histamine may increase the binding interactions to the imidazole binding region

•An extra methyl on the the end thiourea group made it a stronger antagonist (probably tried many variations)

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Strategy

Convert the side chain of burimamide to a more e-withdrawing group

Varying basicity of the imidazole ring

Thiaburimamide – S has slightly longer bonds, slightly more polar (Kp = partition coefficient, more later)

pKa = 6.25Increase in antagonist activityNon-ionised imidazole is favouredIonization 7%

Compare:

e- withdrawing

N N

S

SN

N

CH3

HH

H

H H H


N

N

NH3

H

N

N

HHistamine (pKa 5.74)

Ionization 2% of imidazole ringBurimamide (pKa = 7.25)

Ionization 40% of imidazole ring

e- withdrawing e- donating

Imidazole (pKa 6.80)Ionization 25%

(H is reference group)

H N N

S

N

N

CH3

HH

Tautomer studies of the imidazole ring

RN

N

H

B H

RN

N

H

H

RN

N

H

H

B

RN

N

H

I III II

Tautomer I vs tautomer II

•Favoured tautomer for histamine is I•Inductive effect decreases with distance•N is less basic than N

•N is more likely to be protonated•Favoured tautomer for thiaburimamide is also tautomer I

I III II

N

N

H

R

inductive effect of histamine


Strategy

•Increase the basicity of N relative to N to further increase the percentage population of tautomer I vs tautomer II

•Add an electron-donating group to the imidazole ring closer to N than to N

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Metiamide

Notes•10 fold increase in antagonist activity versus burimamide

Tautomer studies

N N

S

SN

N

CH3

HH

HCH3

e- donating

e- withdrawing

10 fold increase in antagonist activity versus burimamide•Electron-donating effect of methyl group is more significant at N

•Increases basicity of N

•Favours tautomer I over tautomer II•But, increases in pKa to 6.80 •Increase in ionization to 20%•Increase in the population of tautomer (I) outweighs the increase in population of the ionised structures (III)

•Unacceptable side effects - kidney damage


•The increases in activity for thiaburimamide and metiamide may be due to a conformational effect

•The thioether link increases the length and flexibility of the side chain•This may lead to increased binding•The methyl substituent may orientate the side chain into the active conformation –i.e. the methyl group acts as a conformational blocker

Alternative rationales

Substituted oxygen for sulfur in the side chain to make it more electron withdrawing

HN

NO

N

S

NMe

HN

NO

NHS

NHMe

H bond?HN

NO

N

S

NMe

OH

H

H

O

HH bonds?

•Less potent than burimamide despite the side chain being more electron withdrawing, should be less ionized

Possible explanations•The ether link is smaller and less flexibleTh th b i l d i ‘b d’ h d b d

H HOxaburimamideN

H Hpossible change in shape because of

H bonding with N-H?possible desolvation cost due to stronger H bonds with water?


•The ether may be involved in a ‘bad’ hydrogen bond•There may be an energy penalty involved in desolvating the oxygen prior to binding

40

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21

•The side effects of metiamide (decrease in white blood count) may be due to the thiourea group

•The thiourea group is not a natural functional group•Replacing thiourea with a natural functional group may remove the side effects

From metiamide to cimetidine

RN N

S

CH3

HH

RN N

O

CH3

HH

RN N

N

CH3

HH

H

Thiourea - Toxic side effects, few out of 700 patients had granulocytopenia (lo hite blood cells)

UreaDrop in activity

5% as acti e

Guanidinium,(positive side chain)

Drop in acti it ( 5% as acti e)


Conclusions

•First guanidine analogue to be a pure antagonist•The longer 4C chain pushes the guanidine unit beyond the agonist binding region, but not beyond the antagonist binding region

41

(low white blood cells) 5% as active Drop in activity, ( 5% as active)but no agonist activity!

From metiamide to cimetidine wrong compounds

Binding interactions for the 4C extended guanidine

H2N

NH2

+an antagonist

binding regionan antagonist

binding region

Binding as an antagonist

N

N

H S

NH+

N

N

H

S

NH

NH2

H2N

+

+

imidazole ringbinding region agonist

binding regionagonist

binding region



was goodNot binding as an agonist was good

42

+

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22

Strategy:•Retain the guanidine group, but try to remove the positive charge (use dipoles instead)•Guanidine is a natural group present in the amino acid arginine•Increase activity of drug by making the guanidine group neutral•Add a strong electron-withdrawing group to decrease basicity (many tried)•(NO2 and CN), both showed similar antagonist activity

From metiamide to cimetidine

N N

N

SN

N

CH3

HH

HCH3

RN N

N

CH3

HH

HH H

pKa 12.5 pKa 11.5

RN N

N

CH3

HH

H

pKa 8 pKa 7.5

OH CH NH

O

RN N

N

CH3

HH

H

O

NH2

NO

H


RN N

N

CH3

HH

OH

pKa 7

RN N

N

CH3

HH

CH

pKa -0.4

RN N

N

CH3

HH

NH

pKa -0.9

RN N

S

CH3

HH

pKa -1.2

CH3 Obody pH 7.4

H

Properties•Comparable activity to metiamide

id ff

Cimetidine(Tagamet)

Electron-withdrawingcyano group

•Fewer side effects•Inhibits H2-receptors and lowers levels of gastric acid released•Marketed in 1976, greatly reduced surgeries•Biggest selling prescription drug until ranitidine (1981)•Metabolically pretty stable•Inhibits cytochrome p450 enzymes (side effect)•Drug-drug interactions with diazepam, lidocaine and warfarin (side effect)•More recent studies suggest it may help chronic tendenitis of the shoulder and asa supplemental drug in colorectal cancer


a supplemental drug in colorectal cancer

RN

N

HCH2

H

Fe+4

O

RN

N

HCH2

Fe+4

O

H

RN

N

HCH2

OH

metabolites further oxidation possible

RN

N

HH

Fe+3

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Cimetidine (Tagamet)

•The cyanoguanidine group acts as a bio-isostere for the thiourea group

N

S

N

CH3

HC

N

S

S

N

CH3

H

•Both groups are planar and of similar geometry

•Both groups are polar but essentially neutral

B h h hi h di l

N NN3

HH

N NN

HH


•Both groups have high dipole moments

•Both groups have low partition coefficients (Kp values, more water soluble)

•The cyanoguanidine group is weakly acidic and weakly basic - amphoteric

•The cyanogaunidine group is not ionised at pH 7.445

•The favoured tautomer is the imino tautomer

New Consideration - Possible tautomers of the cyanoguanidine group (Cimetidine = Tagamet)

NC

N

NC

N

NC

NH H

•The electron-withdrawing effect of the CN group is an inductive effect•The inductive effect is felt most at the neighbouring nitrogen

RN N

CH3

HH

RN N

CH3

H

RN N

CH3

H

I

Amino Tautomer

II

Imino Tautomer

III

Amino Tautomer


g g g•The neighboring nitrogen is least likely to form a bond to hydrogen•The imino tautomer allows pi resonance with the cyano substituent (and N lone pairs below)

46

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The cyanoguanidine group – possible conformational isomers (and configurational?)

RN N

N

H

CHH

CN

Z

HN N

N

H

CHR

CN

HN N

N

CH3

CN

Z

RN N

N

CH3

CN

Z

Drawn with "CN" on the right (same as CH3). All are presumed to be flat.

EE E

ZE

steric interaction

CH3H CH3R HR HH(Z,E) (E,E) (E,Z) (Z,Z)

HNN

N

R

CN

EZ

HNN

N

H

CN

EE

CH3

NN

N

H

CN

ZE

CH3

NN

N

R

CN

Z

Drawn with "CN" on the left (same as R). All are presumed to be flat.

steric interaction

Z

steric interaction


•Notes•The E, E and Z,Z conformations are not favoured because of steric interactions (X-ray and NMR evidence support this)

•Bad news for the chelation bonding theory because Z,Z conformation is not favored•Chelation to the one carboxylate group requires the E,E or the Z,Z conformation

47

H CH3

(Z,E)R CH3

(E,E)R H H H

(E,Z) (Z,Z)steric

interaction

The cyanoguanidine group – new idea as to possible binding modes

N

steric interaction - not favored

Old idea for interaction atactive site had 2 H bonds.

RN N

N

CH3

HH

CN

Z

(Z,Z)

Z

H bondsH bonds


O O

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25

Rigidification nitropyrrole analogue

N

N S

CH3

N

H

H

N

N

OO

Z

E

•Unable to adopt the E,E or Z,Z conformation•Strongest analogue of cimetidine (antagonist)•Locked into the active conformation•Can only interact with two separate H-bond acceptors in the antagonist binding region

H


Desolvation theory – would an increase in hydrophobic character help activity?

R G

HO

H

O

H

O

HR G

DesolvationEnergy penalty

(Cost)

R GBinding

Energy released(Gain)

•A guanidine unit is highly polar and highly solvated•Solvated water must be removed prior to binding •An energy penalty is involved•The ease of desolvation may affect strength of binding and activity•A urea group is more hydrophilic than a cyanoguanidine groupM l i l ti it f th l

HO

H

hydrophilichydrophobic


•May explain lower activity of the urea analogue

50

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26

log Poct/H2O = log [neutral compound]1-octanol[neutral compound]water

log Doct/H2O = log [all forms compound]1-octanol[all forms compound]water

at specific pH values

The partition-coefficient (P) or distribution-coefficient (D) is the ratio of concentrations of a

Reminder – partition coefficient

The partition coefficient (P) or distribution coefficient (D) is the ratio of concentrations of a compound in a mixture of two immiscible phases at equilibrium.

These ratios are a measure of the difference in solubility of the compound in two phases (water and 1-octanol).

The partition-coefficient generally refers to the concentration ratio of un-ionized species of compound whereas the distribution-coefficient refers to the concentration ratio of all species of the compound (ionized plus un-ionized) and depends on pH.


The distribution coefficient is a partition coefficient at a specific pH value.

The partition coefficient measures how hydrophilic or hydrophobic a chemical substance is. Hydrophobic drugs with high octanol/water partition coefficients are mainly distributed to hydrophobic areas such as lipid bilayers of cells, while low octanol/water partition coefficientsare found primarily in aqueous regions such as blood serum.

Solubility and partition coefficients of straight chain functional groups in 100 g water

OH

CH3

OHOH OH

100% miscible

0.11 mol7.9g

0.030 mol2.6g

0.0058 mol0.6g

0.0008 mol0.09g

log Poct/H2O =

100% miscible

100% miscible

solubility =

-0.74 -0.38 +0.25 +0.84 +1.51 +2.03 +2.62

C5H11OH C6H13OH C7H15OH

0.0058 mol0.6g

0.0008 mol0.09g

+2.97 +4.02

C8H17OH C9H19OH

OO O O O O O O

H3CCC

100% miscible

4.9g

log Poct/H2O =

100% miscible

100% misciblesolubility =

-0.54 -0.32 +0.33 +0.79 +1.39 +1.92 +2.6(guess)

+3.05

OH OH C2H5

COH C3H7

COH C4H9

COH C5H11

COH C6H13

COH C7H15

COHH

100% miscible

1.1g 0.2g(guess)

0.07g

O

C

O

100% 100% 100%

H H

O

H

OO

H

O

H

100% 27soluble (?)

O

H

O

6100%


100% miscible

log Poct/H2O =

miscible misciblesolubility =

+0.35 +0.45 +0.59 -0.24+0.88 +0.29

100%miscible

27gsoluble (?)

+1.3(guess) +0.84

6gmiscible

web site with lots of partition coef. values: https://www.nist.gov/sites/default/files/documents/srd/jpcrd367.pdf

On-line partition coefficient calculator: http://www.molinspiration.com/services/logp.html

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27

There is good correlation of calculated partition coefficients with experimental partition coefficients

log Poct/H2O = log [compound]1-octanol[compound]water

Reminder

1.0

1.5

log D


What might a distribution coefficient curve look like for the following compound?

0.5

0.0

-0.5

-1.0

-1.5

pH2 4 6 8 10 12 14

OH

O

H2N

Strategy•Increase the hydrophobic character of the planar aminal system•Implies less solvation by water•Implies less of an energy penalty associated with desolvation•Implies easier binding at active site and a stronger activity

Desolvation theory - hydrophobic analogues

SN N

CH3

XN

N

CH3H

Aminal system (Z)

H H

•Implies easier binding at active site and a stronger activity

Result•Antagonist activity of analogues increases as hydrophobic character increases

Lipinski’s rules•Lipinski's rules state (rules of thumb)•No more than 5 hydrogen bond donors (the total number of N-H and O-H) •No more than 10 hydrogen bond acceptors (all N and O atoms)•A molecular mass less than 500 daltons (some say < 300)•An 1 octanol/water partition coefficient log P < 5 (some say log P < 3)


•An 1-octanol/water partition coefficient, log P < 5 (some say log P < 3)•There are many exceptions to Lipinski's Rules.•Lipinski said, in general, an orally active drug has no more than one violation and Veber’s rules•Polar surface area (all the O and N < 140A2 and < 90A2 for the BBB) and •The number of rotatable bonds (< 7-10) has been found to better discriminate between compounds that are orally active and those that are not

Veber’s paper: J. Med. Chem. 2002, 445, 2615-2623https://pdfs.semanticscholar.org/8493/576a7927322ebb79c353bc1c1100a186eb50.pdf

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CHNO

Desolvation theory - hydrophobic analogues

‘Outlier’NCN

NHMeHNSNNO2

log (Act)

Result•Antagonist activity of analogues increases as hydrophobic character increases

.HN NHMe

CHNO2

HN NHMe

SNNO2

NHMeHN

NH2

NNO2S

NH2HN

HN NH2

NCN

O

NHMeHN

HN

N

NO

HN

N

NH

O

HN

...

..

..

..

6.0

5.0


Log (activity) = 2.0 log P + 7.4

HN NH2

ONH ..

-0.6-1.0-1.4-1.8

log P of HZ

4.0

55

OCN NO2

RNH

NH

NO2

CH3

log A = 5.5log P = -1.4

Desolvation theory - hydrophobic analogues vs. activity

RNH

NH

O

RNH

NH

N

R

N

R

S

R

O

RNH

NH

N

CH3

NO2

RNH

NH

N2

CH3

R

NCN

CH3R

NH

NH

S

CH3

N

O

log A = 4.6log P = -1.35

log A = 5.8log P = -0.8

log A = 6.0log P = -0.7

log A = 5.0log P = -0.95

log A = 6.1log P = -0.8


Log (activity) = 2.0 log P + 7.4

NH

NH2

RNH

NH2NH

NH2 NH

NH2RNH

NH

log A = 4.1log P = -1.6

log A = 5.3log P = -1.15

log A = 3.9log P = -1.5

log A = 5.4log P = -0.9

log A = 5.3log P = -1.1

Greater activity than expected ?Lower activity than expected ?

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29

Dipole moment theory – dipole-dipole interactions

•A dipole-dipole interaction takes places between the drug and the binding site on approach of the drug

•The dipoles line up and orientate the drug

NMe

H

O2N

NH

R

Approach and orientation

O2N

H

Strong hydrogen bonding

•Good interaction with the binding site occurs if the binding groups are positioned correctly with respect to the binding regions - results in good activity

•Poor interaction occurs if the binding t iti d tl ith

DipoleMomentsH-Bonding regions

Receptorsurface

NMe

H

NH

R

Receptorsurface

NN

OApproach and orientation Weak hydrogen bonding

ideal


groups are not positioned correctly with respect to the binding regions - leads to poor activity

57

NH

NHR

Receptorsurface

NN

H

O

NHR

Receptorsurface

less than ideal

•The orientation of the dipole is more important than its strength•Log (activity) = 9.12 cos + 0.6 log P -2.71

QSAR study including dipole-dipole interactions

30o

Ideal dipoleorientation

Observed dipoleorientation

•Activity increases as hydrophobicity increases (log P)

HN N

X

R H


•Activity increases as hydrophobicity increases (log P)•The ideal angle of the dipole moment = 30o

•At 30o, = 0o and cos = 1•At 30o, Log (activity) = 9.12 + 0.6 log P - 2.71 •When dipole moment does not equal 30o, cos < 1 and activity falls

58

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30

CH3

NN

NC

H

HR

HN N

N

O

R H

HN

N

N

O

R H

HN N

R H

N

O

O

CH3NN

NN

H

HR

N O

O

= 13o

H N

= 13 = 13.1

= 2o

= 13.1 = - 6o

= 16.7 = 27o

= 14.2 = 33o

= 15.1

log A = 9.12 cos + 0.6 log P - 2.7

A = activity = deviation of angle of dipole moment from vertical (receptor site?)P = partition coefficient (related to solubility in water vs. 1-octanol

higher activity higher

activityhigher activity

lower activity

lower activity


CimetidineN N

N

SN

N

H

CH3H

HC

N

Ranitidine (Zantac, Glaxo) Glaxo merged with SmithKline

O

N SN N

Ranitidine

1

2

34

5

H

H

CH3

N N

N

SN

N

H

CH3H

HC

NCimetidineN

O

O

•Contains a nitroketeneaminal group (other flat groups will work too)•Different heterocyclic ring, has a furan ring•Fewer side effects•10 times more active•Longer duration of action•Replacing sulfur with methylene (CH2) reduces activity•Placing sulfur next to ring reduces activity•Replacing furan with a more hydrophobic ring lowers activity•2 5 disubstitution pattern works best


•2,5-disubstitution pattern works best•The methyl groups on the nitrogen can be varied without lowering activity•That same N,N-dimethylaminomethylene substituent on Cimetidine lowers activity•Methyl substitution at position 3 on the furan ring eliminates activity•Methyl substitution at position 4 increases activity (indicates a different sort of interaction than Cimitadine)

•Introduced in 1981, was making over $7,000,000 per day•Took over from Cimetidine as the most widely sold prescription drug in the world 60

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31

Famotidine (Pepcid)

N

SN

NH2

H2NS

N N

Famotidine

1

2

3 4

5

H

H

CH3

N N

N

SN

N

H

CH3H

HC

NCimetidineS

O

O

NH2

guanidine group

thiazole ring

sulfonylamidine group

•Different heterocyclic ring, thiazole ring•30 times more active than Cimetidine•Side chain of sulfonylamidine group, but not essential, needs to have a

dipole moment and be able to hydrogen bond, more variety possible•Side chain length can be 4-5 atoms•Replacing S with CH2 in side chain increases activity•Methyl group at position 4 decreases activity•3 of the 4 hydrogen atoms on the guinidine group are required for activity•Has no effect on cytochrom P450 and does not appear interact with other drugs

g


•Has no effect on cytochrom P450 and does not appear interact with other drugs•Pepcid is also used with dogs and cats with acid reflux•Pepcid is used with H1 antagonists for severe urticaria•Relief of heartburn, acid indigestion, and acid reflux (GERD)•Part of a multidrug regimen for Helicobacter pylori eradication (in combination with antibiotics) •Given to surgery patients before operations to reduce the risk of aspiration pneumonitis.•It has even been used as a co-drug in treatment-resistant schizophrenia

•About 80% of stomach ulcers are healed in 4-6 weeks of treatment with all of these drugs

Proton pump

Receptors

Cck2H2

M3

ATP ADP + Pi

Parietal Cells, the Proton Pump and Inhibitors (PPI)

Lumen of the stomach

Ion channels

Canaliculus

The proton pump•Pumps protons out of the parietal cell and potassium ions back in(H+, outside) / (H+, inside) 3,000,000 / 1 [highest ion differential in the body]

•Requires energy - provided by hydrolysis of ATP to ADP, catalysed by ATPase

H+ +K

HCl

Cl-


•The proton pump is also called H+/K+-ATPase•Chloride ions depart through a separate ion channel•HCl is formed in the canaliculus•The potassium ions exit the parietal cell as counter ions for the chloride ions and are then pumped back in

•A separate potassium ion channel is used for K+ ions leaving the cell

62

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Proton Pump Inhibitors

N

OH C O

S

OHN

N

O F

F

methylsulfinyl'linker'

benzamidazole

pyridine N S

OHN

N

OCH3


benzamidazole

pyridine

H3C

OH3C O

H3CPantoprazole OH3C O

H3COmeprazole

N S

OHN

N


benzamidazole

pyridine N S

OHN

N


benzamidazole

pyridine


O CH3 LansoprazoleF3C

O CH3 Rabeprazole

OH3C

•All of these are prodrugs, minimal side effects until they reach their target•Activated by the strongly acidic conditions (pH < 4) found in the canaliculae of parietal cells in the stomach wall

Mechanism of inhibition

N

SHN

N

O

OCH3

H+N

SHN

N

O

OCH

OCH3

N

N

N

OCH3

H

S

O

B H

HB

pH < 4

N OCH3OCH3

B H

HOCH3

spiro intermediate

B H

N

OCH3

N

OCH3

SN

N

OCH3

SS


N

N

OCH3

H

S

HO

sulphenic acid intermediate

N

B H

N

OCH3

B

ProtonPump

S

H

B

B H

HN N

OCH3

SS

ProtonPump

Pyridinium sulphenamide structure

H

OH

irreversibleinhibition

(covalent binding)

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33

•Originally an antiviral drug

Design of omeprazole (Losec)

The lead compoundN S

NH2

CMN 131

Originally an antiviral drug•Inhibited gastric acid secretion (side effect)•Liver toxicity due to the thioamide group (side effect)•Many derivatives were made to try and overcome this

Modification of the thiourea groupN

S

H 77/67 HN

N


•Also inhibited gastric acid secretion (desired effect)•The pyridine ring and bridging CH2S moiety are important to activity•Many “heterocycle–X-Y-heterocycle” two atom bridges were tried•Left side pyridine and -CH2-S- bridge worked best, but right heterocycle was changedbenzimidazole

65

H 77/67 HN

Modify the imidazole ring


N

S

H 124/26HN

N

benzimidazole

pyridine

Increase in activity due to the benzimidazole ringSulfoxide metabolite had increased activity over H 124/26

Drug metabolism studiesN

S

HN

N

O


•Timoprazole formed by oxidation of sulfur on of H124/26•Timoprazole was the active drug (prodrug)•Pyridinylmethylsulfinyl benzimidazole structure•Side effect – inhibited iodine uptake by the thyroid gland, so no clinical trials•More analogs were synthesized to get around the iodine problem

66

Timoprazole

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34


N

S

HN

N

O

OCH3

O

CH3

•Potent antisecretory properties over long periods of time•No toxic side effects on the thyroid•No other serious side effects using animal studies•Picoprazole was found to be the most effective antisecratory compound ever tested in humans•At this point (1977) the proton pump was discovered and identified as the target of picoprazole•Various substituents were tried on the pyridine ring to make it more basic/nucleophilic

Picoprazole

OCH3

CH3


Add substituents to the heterocyclic rings

67

Substituents varied on the pyridine ring


N

S

HN

N

O

OCH3

O

CH3

OH3C

H3C

•Substituents which increase the basicity/nucleophilicity of the pyridine ring are good for activity•Consistent with the mechanism of activation•Methyl substituents at the meta position have an inductive effect•Methoxy substituent is more effective at para position than meta position because of resonance effect

H 159/69CH3

NH3C

NH3C

NH3C

NH3C


•H159/69 is potent but chemically too labile (unstable in vivo)

68

R

CH3

OH3C

R

CH3

OH3C

R

CH3

OH3C

R

CH3

OH3C

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35

Substituents varied on the benzimidazole ring

•Substituents were varied to get the right balance of potency, chemical stabilityand synthetic accessibility

•Omeprazole was found to have the best balance


N OH3C

•Launched in 1988 by Astra•World’s biggest selling drug (over $6 billion in 2000 alone, > $16,000,000 per day)•Patents ran out in 2001 (Europe and US)

S

Omeprazole

HN

N

OCH3

OH3C

CH3


Esomeprazole (Nexium)•Omeprazole has an asymmetric centre•The S-enantiomer has better potency and pharmacokinetic profile•Undergoes less metabolism than the “R” enantiomer so maintains higher levels of the drug in the body•Example of chiral switching, started a new patent•The “R” enantiomer was approved in the U.S. In 2009 as Dexlansoprazole (another patent)

N

S

Nexium"S" enantiomer of Omeprazole

HN

N

O

CH3

OH3C

H3C

CH3

O

H2 Metabolites


N

S

HN

N

O

CH3

OH3C

2C

CH3

O N

S

HN

N

OCH3

OH3C

CH3

O

Metabolites

HO

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36

Synthesis of Omeprazole

O

N

S

HN

N

OCH3

OH3C

CH3

NaOH

N HS

HN

N

O

CH3

OH3C

CH3

Cl

H3C H3C

pyridine benzimidazolei

N

S

HN

N

OCH3

OH3C

CH3

O

O l

ClO

OH

meta chloroperbenzoic acid(mCPBA)

H3C

portion portion


Omeprazole

Features of Helicobacter pylori

•Spiral, curved bacterium•Grows best in oxygen concentrations of 5%•Naturally present in the stomachs of many people•Attaches to a sugar molecule on the surface of the cells lining the stomach wall•The organism secretes proteins and toxins that inflame the stomach lining•Responsible for the recurrence of ulcers•The organism is protected by the mucus layer •A pH gradient across the mucus layer means that the pH is near neutral at the stomach lining•The helicobacter pylori bacteria was discovered in the contents of Otzi's stomach (5000 year old frozen ice man).

Helicobacter pylori, is a gram-negative, microaerophilic bacterium found usually in the stomach. It was identified in 1982 and found that it was present in a person with chronic gastritis and gastric ulcers, conditions not previously believed to have a microbial cause. It is also linked to the


ulcers, conditions not previously believed to have a microbial cause. It is also linked to the development of duodenal ulcers and stomach cancer. Over 80% of individuals infected with the bacterium are asymptomatic, and it may play an important role in the natural stomach ecology.

More than 50% of the world's population harbor H. pylori in their upper gastrointestinal tract. H. pylori's helical shape is thought to have evolved to penetrate the mucoid lining of the stomach.

Individuals infected with H. pylori have a 10 to 20% lifetime risk of developing peptic ulcers and a 1 to 2% risk of acquiring stomach cancer.

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37

pH = 2

Stomach contents

Mucus layer

pH = 4

Features of Helicobacter pylori

H. pylori

pH 4

pH = 7


•Bacterium produces urease enzyme, releases basic ammonia•Neutralises any acid in the local environment of the bacteria

H2N

O

NH2

Urease

Urea2 NH3 + CO2

H2O

•Triple therapy of a proton pump inhibitor and two antibiotics•Antibiotics work better at a higher pH than is normally present in stomach•The proton pump inhibitor is present to raise the pH

Treatment of Helicobacter pylori

ExampleOH

N

S

Omeprazole

HN

N

O

CH3

OH3C

H3C

CH3

O

AmoxicillinMetronidazole

NH2

O

HN

N

S

HO O

CO2H

N

OH

CH3

O2N


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