TARGETS FOR DEVELOPMENT OF ANTI-ULCER AGENTS

ByVamsi rajasekhara reddy

M-Pharmacy 1st Year(Pharmaceutical Chemistry)

CONTENT

FACTORS FOR ULCERATION PHYSIOLOGY OF ACID SECRETION TARGETS OF ANTIULCER AGENTS MECHANISM OF ACTION SIDE EFFECTS

PATHOGENIC FACTORS FOR ULCERATION Imbalance between the aggressive and the defensive factors.Acid secreted by parietal cells is aggressive factor.Gastric mucosa, bicarbonate secretion, prostaglandins nitric oxide are defensive factors

Helicobacter pylori infection.

ACID SECRETION BY STOMACH

Gastric acid secreted by parietal cells. Basolateral membrane of these cells contain 3 main

stimulantsGastrin (from G cells)Histamine (from enterochromaffin cells)Acetylcholine (from vagal efferent)

These stimulants stimulate proton pump Stimulated proton pump translocates from cytoplasmic

vesicles to the secretory canaliculus of the parietal cells Uses energy derived from hydrolysis of ATP, to transport H+

out of parietal cells in exchange for K+

Hydrogen ions combine with Chloride ions to form hydrochloric acid(HCl)

Hydrochloric acid is secreted in to gastric lumen.

Secretion of acid by parietal cells

TARGETS

H2 receptor eg: Cimetidine, Ranitidine, Famotidine Proton Pump eg: Omeprazole, Lansoprazole, Pantoprazole

M1 receptor eg: Pirenzipine, propantheline, Oxyphenonium

Gastrin receptors eg:Misoprostol, Enprostil, Rioprostil

Cell wall eg:sucralfate

Stomach eg: Antacids ( sodium bicarbonate, Magnesium hydroxide )

Helicobacter pylori eg:Amoxycillin, Clarithromycin, Metronidazole

H2 RECEPTOR

ranitidine cimetidine

SAR

Imidazole ring exist in two tautomeric forms. In these form – I to be necessary for maximal H2 antagonist activity.

When R is substituted with methyl group, the activity is potentiated

The other heterocyclics like furan, thiazole enhance the potency and selectivity of H2 receptor antagonism

The ring and terminal nitrogen should be separated by four carbon atom for optimum activity. The shorter chain decrease the activity.

The side chain should contain an electron with drawing substituents and an Isosteric thioether (- S-) link in place of methylene group (- CH2) leads to more active compound.

The terminal nitrogen should be polar, non basic substituents for maximal activity.

Synthesis of Cimetidine

Histamine H2 Receptor Antagonist

Reversible competitive inhibitors of H2

receptor

Highly selective, No action on H1 or H3

receptors

Very effective in inhibiting nocturnal acid secretion ( as it depends largely on Histamine )

Modest impact on meal stimulated acid secretion (As it depends on gastrin, acetyl choline and histamine)

H2 Blockers–Side effects & Interactions

Extremely safe drugs

Mental status changes may occur

Cimetidine inhibits metabolism of estradiol and increase prolactin level

Cimetidine increases concentration of Warfarin, Theophylline, Phenytoin, Ethanol.

PROTON PUMP

Examples

N

CH3CH3

HOH2C

OCH3

SOCl2N

CH3CH3

ClH2C

OCH3

NH2

NH2H3CO

C S

H5C2O

KSN

NH

H3CO

SH+

N

CH3

CH3 OCH3

CH2N

NH

H3CO

S

O

OH

Cl

NaOH

NCH3

CH3

OCH3CH2N

NH

H3CO

S

O

Omeprazole

2 chloromethyl 3,5 dimethyl 4 methoxy pyridine

5 methoxy 2 mercaptobenzimidazole

4 methoxy O

phenylene diamine

potassium ethylxanthate

Proton Pump Inhibitors

Most effective drugs in antiulcer therapy Irreversible inhibitor of H+ K+ ATPase Prodrugs requiring activation in acid environment Weakly basic drugs & so accumulate in canaliculi

of parietal cell Activated in canaliculi & binds covalently to

extracellular domain of H+ K+ ATPase Acid secretion resumes only after synthesis of

new molecules

Poton Pump Inhibitors – Kinetics

Given as enteric coated granules in capsule or enteric coated tablets

Pantoprazole also given intravenously

Half life – 1.5 hrs

Since it requires acid for activation - given 1 hr before meals

Other acid suppressing agents not coadministered

P.P.I. – Side effects & InteractionsExtremely safe drugs

Causes hypergastrinemia which leads to carcinod tumor in rats

But no evidence of such tumors in man

Inhibit CYP 450 & hence metabolsim of warfarin, phenytoin, etc

Pantoprazole & Rabeprazole have no significant interactions

M1 RECEPTORS

N

NH2

Cl

+Cl

O

O2N -H C l

N

NH

ClO

O2N

H2

Raney Ni

N

NH

ClO

NH2

2 0 0 °C

-H C l

N

NH O

NH

ClCOCH2Cl

N(CH3)3

N

NO

NH

OClH2C

-HCl

NH N CH3

N

NO

NH

ON

N

CH3

3-Amino

-

Chloropyridine2 Nitrobenzoyl chloride

M1 RECEPTOR ANTAGONIST

Block M1 receptor at enterochromaffin cells

Donot cross Blood Brain Barrier

Nonselective

Blurred vision, dry mouth, urinary retention

Delay gastric emptying

Eg: Propantheline, Oxyphenonium, Pirenzepine, Telenzepine

GASTRIN RECEPTORS

PROSTAGLANDIN ANALOGUES

Produced in gastric mucosa Inhibits gastrin release Enhances mucosal blood flow Stimulates secretion of mucus and bicarbonates NSAID associated gastrointestinal injury Need multiple daily dosing Diarrhoea, abdominal cramps, uterine

contractions

Eg: Misoprostol, Enprostil Rioprostil

CELL WALL

Mucosal Protective Agents

Sucralfate

Colloidal Bismuth compounds

Sucralfate

In acidic pH polymerises to viscous gel that adheres to ulcer crater

Taken on empty stomach 1 hr. before meals

Salt of sucrose complexed to sulfated aluminium hydroxide

Concurrent antacids, H2 antagonist avoided

( as it needs acid for activation )

Colloidal Bismuth Compounds

Coats ulcer, stimulates mucus & bicarbonate secretion

Direct antimicrobial activity against H.pylori

May cause blackening of stools & tongue

Not used for long periods – bismuth toxicity

Available compounds : Bismuth subsalicylate – in USA Bismuth subcitrate – in Europe Bismuth dinitrate

STOMACH

ANTACIDS

Weak bases that neutralize acid

Also inhibit formation of pepsin

(As pepsinogen converted to pepsin at acidic pH)

Present day antacids :

Aluminium Hydroxide

Magnesium Hydroxide

Duration of action : 30 min when taken in empty stomach

2 hrs when taken after a meal

Side effects : Al3+ antacids – constipation (As they relax gastric

smooth muscle & delay gastric emptying)

Mg2+ antacids – Osmotic diarrhoea .

In renal failure Al3+ antacid – Aluminium toxicity

Antacid – Interactions Adsorb drugs and form insoluble complexes that are not absorbed

HELICOBACTER PYLORI

Eradication of H.pylori

Triple Therapy

The BEST among all the Triple therapy regimen is

Omeprazole / Lansoprazole - 20 / 30 mg

Clarithromycin - 500 mg

Amoxycillin / Metronidazole - 1gm / 500 mg

Given for 14 days followed by P.P.I for 4 – 6 weeks Short regimens for 7 – 10 days not very effective

Some other Triple Therapy Regimens are

Bismuth subsalicylate - 2 tab

Metronidazole - 250 mg

Tetracycline - 500 mg

Ranitidine Bismuth citrate - 400 mg

Tetracycline - 500 mg

Clarithromycin / Metronidazole - 500 mg

Quadruple Therapy

Given when Triple Therapy fails

Omeprazole / Lansoprazole - 20 / 30

Bismuth subsalycilate - 2 tabs

Metronidazole - 250

Tetracycline - 500

FUTURE PROSPECTS

Reversible proton pump inhibitors are currently underdevelopment by the company Astra-Zeneca.

Development of vaccine for Helicobacter pylori is currently being explored.

REFERENCE:

“FOYE’S PRINCIPLES OF MEDICINAL CHEMISTRY” 1019-1024

Essentials of MEDICAL PHARMACOLOGY “K D Tripathi” 587-598

Clinical Pharmacology by “P N Bennett M J Brown” 561-568 An Introduction to Medicinal Chemistry by “Graham L.

Patrick” 642-670 Principles of Pharmacology by H L Sharma K K Sharma”

386-399 http://aac.asm.org/cgi/content/full/48/12/4582?maxtoshow

=&HITS=10&hits=10&RESULTFORMAT=&fulltext=cimetidine+synthesis&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

http://aac.asm.org/cgi/content/full/51/3/831 http://jac.oxfordjournals.org/cgii/content/full/59/1/160

THANK YOU