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Your Speakers 2
*
Darren McKerrecher
Darren obtained his Chemistry degree at Edinburgh, and completed his D.Phil
Peter Astles
Peter completed his Chemistry degree and Ph.D. at the University of Oxford
Dr Ted (AH) Parton
Ted studied Chemistry at Cambridge and gained a PhD in the
with Richard Taylor at York. He joined Zeneca, now AstraZeneca, at Alderley Park in 1997. He has been involved in a number of projects with ADMET challenges, in disease areas as diverse
before spending two years of postdoctoral research with Prof. Leo Paquette at the Ohio State University, USA. He joined Rhone-Poulenc Rorer, now Sanofi, in 1992 learning about
analytical chemistry of insect pheromones at the University of Southampton. He began his career in pharmaceutical development in 1985 at Upjohn Laboratories in challenges, in disease areas as diverse
as cancer, diabetes, obesity, asthma and COPD, and is co-author of more than 50 papers and patents. From 2006-2008, Darren undertook a secondment in AZ Lund (Sweden)
now Sanofi, in 1992 learning about medicinal chemistry and drug discovery while working on several asthma/ inflammation projects. In 2000, Peter moved to Eli Lilly, based at Windlesham in the UK where he is
985 at Upjo abo ato esCrawley. In 1993, he moved to Celltech in Slough, acquired by UCB in 2004, where he is a Director in Pre-clinical PKPD and DMPK Project Support He still enjoyssecondment in AZ Lund (Sweden),
before returning to Alderley Park where he is now Associate Director of Medicinal Chemistry, Project Leader and responsible for chemistry outsourcing
at Windlesham in the UK, where he is a Group Leader in med chem and a project leader in the CNS therapeutic area focusing on Alzheimer’s Disease and schizophrenia.
Project Support. He still enjoys talking with chemists and is delighted to be first author on a patent!
in the Oncology iMED.
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Molecular InteractionsSmall molecules bind to protein targets through a combination of;
Sterics:• Shape complementarity
Electronics:• Energetically favourable interactions• Shape complementarity
(vs natural substrate/ligand)
• Lock and key analogy
• Energetically favourable interactions
Tyrosine
• Lock and key analogy
H-bondscharge transfer interaction
OH
H
O
Tyrosine Kinase hydrophobic
interaction
H-bondN H H
OH
O O
O
N
O
ion-dipoleinteraction
Small molecule inhibitor
-+ion-ion interaction
steric repulsionshape complementarity
O O
NH2H2NH
N
‘How to make the shape of the key fit the lock?’
‘How to maximise these binding interactions?’y
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Historically potency is not everything!Historically potency is not everything!
How many drug targets are there? Overington, John P.; Al-Lazikani, Bissan; Hopkins, Andrew L. Nature Reviews Drug Discovery (2006), 5(12), 993-996
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Pharmacokinetics Physical &Pharmacokinetics Physical &Pharmacokinetics, Physical & Pharmacokinetics, Physical & Pharmaceutical propertiesPharmaceutical propertiesa aceut ca p ope t esa aceut ca p ope t es
in Medicinal Chemistryin Medicinal Chemistry
Potential drugs...Potential drugs...or merely good or merely good ligandsligands??
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DMPK & Candidate DrugsCandidate Drugs need good predicted human PK & minimal drug-
drug interaction potential to have a chance of progress
Interactions(Cyps)
Drug Design Criteria for Medicinal Chemists to be worried aboutDrug Design Criteria for Medicinal Chemists to be worried about
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ADME Overview
Permeability Efflux Aqueous Renal Metabolic Biliary Protein TissueAbsorption Elimination Distribution
CNSPermeability Efflux Aqueoussolubility
Renalexcretion
Metabolicstability
Biliaryexcretion
Protein binding
Tissuebinding
CNSpenetration
fabs Cl VDabs Cl VD
%F t1/21/2(poor/med/high) (once, twice or more daily)
And once you’ve cracked all that, compounds can still be toxic!
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Absorption
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9Absorption from an oral doseHow do you know you have a problem?o do you o you a e a p ob e
Compound A i.v. bolus injection 1 mg/kg
entra
tion
p j g g• Good plasma exposure (area under curve AUC)• Metabolic or other plasma clearance appears low
Compound A oral dose (p.o.) 10 mg/kg
asm
a co
nce
g/m
l)
p (p ) g g• Low plasma exposure (AUC)• Unchanged parent drug may appear in faeces
Time after dose (h)
Pla
(ng
Oral Bioavailability (F)= fraction of the dose which makes it to the systemic circulation(Combination of absorption & clearance)(Combination of absorption & clearance)
F% = AUC po / doseAUC iv / dose
x 100
Compound A has low oral bioavailability
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AbsorptionThe process by which a drug moves from its site of
administration to the systemic circulation
dissolve survive range of pH (1.5-8)
MOUTH
Portal vein
Oral dosing survive intestinal flora/fauna cross membranes
INTESTINESTOMACH
relative surface area ~1pH ~1 INTESTINE BLOOD
relative surfacearea ~600
pH ~7
Liver
MetabolismGut wall
pH ~7
Adapted from a slide by Rhona Cox
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Absorption – sources of the problem
packed organicsaq. soln.
efflux
lipid bi-layer Drug in blood dissolving instomach/intestine i
efflux
stomach/intestineSurviving pH 1-7
crossingmembranes(permeability)
•Solubility•InstabilityInstability•Permeability•Efflux
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Absorption - SolubilitySolubility can be measured in a number of
different media: eg, water, (simulated gastric fluid) and pH values: pH 7 4 (blood) pH 6 5 (small intestine – major site of absorption)pH values: pH 7.4 (blood), pH 6.5 (small intestine – major site of absorption)
Typical assays for measuring solubility/ dissolution rate:• “Traditional” solubility / dissolution measurementsTraditional solubility / dissolution measurements
- Thermodynamic (equilibrium) measurements- values will depend on the crystalline form of the compound- caution with amorphous solids!p- lower throughput
• High throughput turbidometric measurementsg g- Kinetic measurement from DMSO solutions- for newly synthesised compounds- quick indication of low solubility
• Calculation/ Prediction from molecular structure- in house and commercial programs available
Caution! Need to be aware of differences between thermodynamic and kinetic solubility
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Solubility is physical chemistry
What factors govern solubility?What factors govern solubility?
“Brick Dust or Greaseballs”:J. Med. Chem. 2007, 50, 5858-5862J. Med. Chem. 2007, 50, 5858 5862
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Solubility vs ClogPScatter Plot
400
300
350
200
250
150
200
50
100
0
1.5 2 2.5 3 3.5 4
Series needs clogP <2.5 for solubility >50µM (~0.025mg/ml)
cLogP
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Predicted vs Observed Aqueous Solubility
-7.5 -5.5 -3.5 -1.5
Series of Lipoxygenase Inhibitors:
-3.5Observed Log(molar solubility)
-5.5
-4.5
-6.5
-7.5
logS = -1.16xlogP - 0.018xMpt + 0.93
r2=0.96
• Mpt reflects energy required to break crystal lattice• LogP reflects energy required for solute to enter aqueous phaseLogP reflects energy required for solute to enter aqueous phase• Lowering melting point and logP increases solubility
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Example: Methylation of amides
S f h l
R1
O
NR2
HR1
O
NR2
MeSurvey of whole company database of solubility
-2 8
Not lipophilicity driven
-3.5
-3
-2.5
ON
Me
5
6
7
Me
-5
-4.5
-4
og(S
olub
ility
) of C
O
3
4
Clo
gP o
f CO
NM
-6.5
-6
-5.5lo
0
1
2
Mean change = +0.61
-7-7 -6.5 -6 -5.5 -5 -4.5 -4 -3.5 -3 -2.5 -2
log(Solubility) of CONH
00 1 2 3 4 5 6 7 8
ClogP of CONH
Mean change = +0.34gFor 77% of cases, CONMe is more soluble than CONH
For 82% of cases, CONMe is more lipophilic than CONH
Thanks to: Andrew Leach, AstraZeneca Alderley Park
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The solid state & melting points
20
30
nt
BrCl
X
0
10m
eltin
g po
in ClMeNH2NO2
30
-20
-10
chan
ge in
OHOMeamide methylationaza
-40
-30
-1.5 -1 -0.5 0 .5 1change in logP
aza
change in logP
Average change in logP and MPt for matched pairs (data from Beilstein)
CONMe has than CONHlower average melting point
higher average logP
Thanks to: Andrew Leach, AstraZeneca Alderley Park Journal of Medicinal Chemistry (2006), 49(23), 6672-6682
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The solid state & melting points
NO
NNH
H OMe
NN
NH
Me OMe
t-Bu OO
i-Pr t-Bu OO
i-Pr
3.06
2.842.83
3 06 2.83 2.833.06
Introduction of CONMe eliminates intermolecular H-bonding:lowers lattice energy, lowers melting point & increases solubility
Thanks to: Andrew Leach, AstraZeneca Alderley Park
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Absorption – sources of the problem
lpacked organics aq. soln.packed organics
efflux
lipid bi-layer Drug in blood dissolving instomach/intestine crossing
efflux
Surviving pH 1-7crossingmembranes(permeability)
•SolubilitySolubility•Instability•Permeability
Measure stability in GI fluids/range of pHs
•Efflux
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Absorption: pH ranges and GI stabilityCompounds administered orally will encounter:
• A pH range from 1 to 8 in the GI tractDi ti d b t i l• Digestive and bacterial enzymes
note effect of feeding!
Compounds may be unstable to acid pH range (1-3)- measure stability over time as a measure of pH
of feeding!
measure stability over time as a measure of pH
Compounds may be unstable to lipases, peptidases, esterases etc- use gastric fluid ex vivo or purified enzymesg p y
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Why is pKa important ?Strong Acids
Weak Acids
Strong Zwitterions
Neutrals
Weak Zwitterions
When pH = pKa, 50% charged & 50% uncharged
Many marketed drugs are acids or bases
Bases
Acids, bases and neutrals have very different ADMET properties:
• Adding ionizable groups can enhance solubility (pH dependent)• Adding ionizable groups can enhance solubility (pH dependent)
but...
• Ionized species pass through lipid membranes at a much lower rate than neutrals
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Absorption – sources of the problem
k d i aq. soln.packed organics
efflux
lipid bi-layer Drug in blood
crossing
efflux
Desolvation crossingmembranes(permeability)
•Solubility•Solubility•Instability•Permeabilityy•Efflux
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Permeability is also physical chemistry
What factors govern permeability?What factors govern permeability?
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Lipinski Rule of 5
• Mol Weight > 500
• Poor permeability is more likely when:
• LogP > 5• > 5 H- bond donors (eg OH, NH)• The sum of N and O atoms > 10Adv. Drug Delivery Rev. 1997, 23, 4-25J. Pharm. Toxicol. Methods 2000, 44 235-249
• Since Lipinski’s data set relates to marketed drugs, and• Lead optimisation often involves increasing complexity,• The concepts of ‘lead-like’ parameters and ‘ligand efficiency’ have arisen:
• Mol Weight < 300L P < 3
“Astex Rule of 3” for optimal lead compounds:
• LogP < 3• No. donors < 3• No. acceptors < 3
See: Congreve et al: J. Med. Chem., 2008, 51, 3661 (excellent recent review) & DDT, 2003, 8, 876 (Rule of 3)Teague et al: Angewandte Chemie, International Edition 1999, 38, 3743 (lead-like)
No. acceptors 3
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Larger molecules need more lipophilicity to t bpermeate membranes.
•Defining optimum lipophilicity and MW ranges for drug candidates – MW dependent logD limits based on permeability. Waring, Bioorg. Med. Chem. Lett., 2009, 19, 2844 •Lipophilicity in drug discovery. Waring. Expert Opin Drug Discov. (2010) 5(3) 235
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Optimal Window & Development Compounds26
• Development compounds often lie within optimal window – ‘Golden Triangle’• More polar compounds allowed by lower MWt
Does this lead to increased chance of success?• Does this lead to increased chance of success?
See also: Johnson, T.; Dress, K.R.; Edwards, M. Bioorg. Med. Chem. Lett. 2009, 19, 5560
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Impact of Molecular Shape / Complexity
• A simple & interpretable measure of the complexity of molecules is carbon bond saturation, as defined by Fraction sp3 (Fsp3) where:
• Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success (Lovering, Wyeth)J. Med. Chem. 2009, 52, 6752–6756
p ( p )
• Significant enrichment of increased saturation as compounds progress through clinical testing:• Fsp3 correlates with improved solubility (& reduced Mpt):
•The impact of aromatic ring count on compound developability – are too many aromatic rings a liability in drug design? (Ritchie & Macdonald, GSK) Drug Discov. Today 2009, 14, 1011-1020g ( , )
• As aromatic ring count increases:• Lipophilicity increases• Solubility decreases (even when clogP remains constant)• Protein binding, Cyp inhibition & hERG liability increase (later...)
Drug Discov. Today 2009, 14, 1011 1020
g, yp y ( )• >3 Ar rings correlates with poorer compound developability & increased risk of attrition in development
• Molecular flexibility (# of rotatable bonds) has also been shown to correlate with oral bioavailability (Veber, GSK)J. Med. Chem. 2002, 45, 2615
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H-bonding & Permeability28
1 donor green, MDCK against logD: S c a t te r P lo t
50
Minimising number of H-bond donors is a good strategy to improve permeability:
g ,2 donors red, >2 grey
5
10
25
1
5
0.5
A P_ A V G _ L O G D0.5 1 1 .5 2 2 .5 3 3 .5
OHStructural changes:
O OOH
Removal of donor
N
NRemoval of donor improves permeability but increases logD outside target range
logD increase can be offset by introducing heteroatoms
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Polar Surface Area (PSA)
The Polar Surface Area (PSA) of a molecule is defined as the area of a molecule’s van der Waal’s surface that arises from O or N atoms, or hydrogen atoms attached to O or N atoms.
Scatter Plot
metoprololnordiazepam
100
Human intestinal permeability v PSA
diazepamoxprenololphenazone
oxazepamalprenolol
practolol
pindolol
ciprofloxacin
80
100
Paroxetine 39A2p
metolazone
tranexamic acid
atenolol
60
Used for IBDsulpiride
mannitol
foscarnet
sulfasalazine
20
40 Used for IBD (local GI effect)
Sildenafil 109A2
PSA (A2)
olsalazinelactulose
raffinose
25 50 75 100 125 150 175 200 225 250
0
Veber reported that best probability of good oral bioavailability if PSA < 140 A2
J. Med. Chem. 2002, 45, 2615
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Maximum Absorbable Dose (MAD)
MAD (mg) = S x Ka x SIWV x SITTPharmaceutical Research, Vol. 13,1996,1795-1798
S = solubility (mg/ml) at pH 6.5Ka = intestinal absorption rate constant (min-1)(derived from rat intestinal perfusion expt - similar to man)SIWV = small intestine water volume ~ 250 ml for manSIWV = small intestine water volume ~ 250 ml for manSITT = small intestine transit time ~ 270 min (4.5h) for man
MAD = quantity absorbed if the small intestine were saturated with drug for 4.5h
Impact of MAD:
q y g(eg, dose 10g/kg to saturate small intestine, how much of the dose will be absorbed)
Compound Ka Solubility MAD
pTake two compounds with projected human dose of 70 mg
Cmpd A 0.001 min-1 5 mg/ml 337 mg
C d B 0 03 i 1 0 001 / l 2Cmpd B 0.03 min-1 0.001 mg/ml 2 mg
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Developability Classification System
Compounds in class IIb take on average twice as long (ie 2 years longer) to fail in developmentCompounds in class IIb take on average twice as long (ie 2 years longer) to fail in development.
Time is expended on having to do very expensive human studies to only discover that the compound can not be progressed because of, for instance, lack of efficacy due to lack of exposure of compound to target. This would have been found out earlier in animal studies if the compound had better properties that could
The developability classification system: Application of biopharmaceutics concepts to formulation developmentJames M. Butler, Jennifer B. Dressman. Journal of Pharmaceutical Sciences, 99(12),4940–4954, 2010
This would have been found out earlier in animal studies if the compound had better properties that could have enabled more effective earlier decision studies.
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Balancing Solubility & Permeability32
ON
O
NM O
CO2H S
NO
N
O
MeOWant to remove
O
NH
N
F
MeO
logD 1.4
N
O
NH
F
MeO
logD 4.1PPB ↑, Soly ↓
acid functionality
F F Solubility-limited exposure?
CombineSought toincrease solubility
S
NO
NH
O
MeOCombineO
NH
O
NMeO
CO2H
O
MeO2S
NeutralsTarget logD range 2-3
Balance Soly & Absorption
O
MeO2S
logD –0.4PPB ↓, Soly ↑Absorption-limited
E l f d t b l bilit & l bilit t ti i i i
y pExcellent exposureexposure?
Example of need to balance permeability & solubility to optimise in vivo exposure
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Absorption – sources of the problem
aq solnpacked organics aq. soln.packed organics
efflux
lipid bi-layer Drug in blood dissolving instomach/intestine crossingSurviving pH 1-7
gmembranes(permeability)
•Solubilityy•Instability•PermeabilityEffl•Efflux
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Active Transport
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Caco-2 Model of Absorption
120 TESTOSTERONE
100
120 TESTOSTERONEMETOPROLOL
GLUCOSEPHENYLALANINEGLYCINE-PROLINE(%)
80PROPRANOLOL
QUINIDINE
GLYCINE PROLINE
uman
s
O
OH
NH NOH
60 CIMETIDINESUMATRIPTAN
ATENOLOLon in
Hu
CONH2
ON
N
MeO
20
40ERYTHROMYCIN
bsor
ptio
OH
OH
0 01 0 1 1 10 1000
20MANNITOL
PEG4000
Ab OH
OH
OH OH
OH
0.01 0.1 1 10 100
Papp cm/sec x 106
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Uptake Transporters• Uptake transporters enhance the absorption of drug molecules from the intestine (Current Drug
Metabolism 2004, 5, 109-124)
p p
• They may also enhance the distribution of drugs into certain organs such as the brain and into hepatocytes to enable metabolic or biliary clearance
• In contrast to passive diffusion, active transport can be saturated• Finite number of transporter protein molecules on cell
• Examples of uptake transporters and their substrates• Examples of uptake transporters and their substrates
• Oligopeptide transporters PEPT1, PEPT2 - enalapril
• Large neutral amino acid transporter (LAT1) - L-dopa
• Monocarboxylic acid transporter (MCT1) – salicylic acid
• Organic anion transporters (OATP1B1 OATP1B3) Fexofenadine• Organic anion transporters (OATP1B1, OATP1B3) – Fexofenadine• Other substrates – statins, Angiotensin II antagonists
O
NO CO2HPh
Ph
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Efflux (P-glycoprotein, P-gp, MDR-1)( g y p , gp, )• Efflux transporters on the intestinal lumen (apical) oppose the absorption
of certain drug moleculesof certain drug molecules
• Mainly a function of a transporter in the cell membrane called P-glycoprotein Abundant in “protective cells BBB intestine liver kidneyglycoprotein. Abundant in protective cells – BBB, intestine, liver, kidney
• Some compounds are a substrate for P-gp– Enter the cell by passive diffusion, some of the compound is
transported back into the intestinal lumen.– No clear SAR but common features emergingg g
• Some compounds inhibit P-gpA i hibit ( il) ill i th b ti f P– An inhibitor (eg verapamil) will increase the absorption of P-gp substrates
• Other efflux transporters exist eg BCRP, MRP2 which effect drug disposition
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Caco-2 cells - Transport ExperimentCaco 2 cells Transport Experiment(efflux measurement)
Apical Apical chamberchamber
cellcell
chamberchamber“Gut”“Gut”
cell cell monolayermonolayer
Basolateral Basolateral chamberchamberchamberchamber“Blood”“Blood”
DRUGDRUG
If Papp B-A > A-B then efflux may be operating
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General Characteristics of P-glycoprotein SubstratesSubstrates
• Lipophilic often with multiple aromatic rings• High Mol Wt (>400) (increased probability for points of interaction)High Mol Wt (>400) (increased probability for points of interaction)• Ampiphilic often with weak cationic group present• Electronegative groups contributing dipole moment• 1-3 H-bond acceptors (N, 0) and/or 1-2 H-bond donors (NH, OH)p ( , ) ( , )
– Alkoxy and Carbonyl are frequent functionalities
• As membrane passive diffusion increases, P-gp pump efficiency ddecreases
• Review – T.J. Raub, Molecular Pharmaceutics, 2006, 3(1), 3-25.
O
O
O
N
O
O
O
OHN
N
NH
SO
N
O
O
omeprazoleN
N
NNH
O
N
NO NH2NH
verapamil quinidineomeprazole
NH
NN O
OHoechst 33342
rhodamine 123
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Pfizer NK2 Antagonists gJournal of Medicinal Chemistry (2002),45(24),5365-5377.
Cl ClCl Cl
NN
NNO
ON
NNO
FS
NH2O
UK-224,671NK2 IC 8 4
FF
UK-290,795NK2 pIC50 = 8.4
clogP = 2.2Mol weight = 545
NK2 pIC50 = 9.4
clogP = 4.1M l i ht 561Mol weight = 545
PSA = 98 A2, HBD = 2
Caco 2 %/h A B/B A = 1/18
Mol weight = 561PSA = 27 A2, HBD = 0
C 2 %/h A B/B A >35/>35Caco-2 %/h A-B/B-A = 1/18Rat %F < 20 P-gp KO mice > 20%
Caco-2 %/h A-B/B-A = >35/>35Rat %F > 80
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41
Absorption – sources of the problemp p
aq. soln.packed organics
lipid bi-layer Drug in blood Dissolving int h/i t ti
efflux
stomach/intestineStable pH 1-7
Crossing membranes(permeability)
S•Solubility•Instability•Permeability•Permeability•Efflux
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logD vs physicochemical parameters
10
g p y p
789
10
Solubility
4567 Solubility
Mol WeightPermeability
1234
PSA
0
logDg
Over-simplification and series-dependent, but can be a useful working guide to chemistryg g y
eg see Smith et al, Med. Research Rev. 1996, 16, 243-266
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In Summary..what you can do:
Poor absorption may be due to :• Poor absorption may be due to :
• Poor solubility• Poor solubility– Reduce lipophilicity/ add polar/ ionizable groups– Reduce melting point (by reducing symmetry, planarity)
• Poor permeabilityI li hili it– Increase lipophilicity
– Decrease polar surface area/H-bonding– Decrease mol weightg
• EffluxI i bilit t d i t f ffl– Increase passive permeability to reduce impact of efflux
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Worked examples…
Solubility of Iressa
NH
Cl
F
H
F
N
N
N Cl
O
ON
N
NH
O
ONO Cl
EGF - RTK IC50 0.009 M
NO
Solubility at pH 7 (phosphate) 3.7 M
Stim. Cell Growth IC50 0.08 MSolubility at pH 3 (phosphate) 2.2 mM
Solubility at pH 1 (HCl) 48 mMSolubility at pH 7 7.2 M
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Solubility and oral absorption HIV t i hibit (J M d Ch 1994 37 3443 3451)HIV protease inhibitors (J. Med. Chem. 1994, 37, 3443-3451)
OHH
O NH
NH
O
OH
O
OH
N NH
OH
O
H
O
OH
NH
IIC50 = 0.3nMNo oral bioavailability in dog
IIIC50 = 7.8 nM15% oral bioavailability in dogNo oral bioavailability in dog
Solubility (pH 7.4) < 0.001 mg/mlclogP = 5
15% oral bioavailability in dog
NH
OH
O
NN
NOHIII
IC50 = 0.3 nMSolubility (pH 7.4) = 0.07 mg/ml
NHO70% oral bioavailability in dogclogP = 2.8Indinavir – marketed for HIV infection
I ti f l bili i ( kl b i i idi )• Incorporation of solubilising groups (weakly basic amine, pyridine) and lowering logP increases oral absorption
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Pfizer Glycine Antagonists
OHNN
Cl NN H
O
SO2Me
Cl NN
O
SO2MeIncrease solubility by reducing
Increase solubility by decreasing
Cl NN
O
N OMe
Cl NH
O
Potency 20nM
Cl NH
O
Potency 3nM
reducing lipophilicity
glattice energy
Cl NH
O
Potency 2.6nMPotency 20nMSolubility <1mg/ml
Potency 3nMSolubility 5-30mg/ml
Potency 2.6nMSolubility >30mg/ml
(thanks to Alan Stobie)
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Intestinal permeability and oral absorptionEndothelin (ET) A receptor antagonists (J Med Chem 1994 37 1553-1557)Endothelin (ET) A receptor antagonists (J. Med. Chem. 1994, 37, 1553-1557)
O O O
CO2H CO HO O
CO2H
CO2HO O
OH
CO2H
O
CO2H
O
CO2H
O
PSA = 75pKa = 4.1logD7.4 = 2.2
PSA = 141pKa = 3.1, 4.1logD7.4 = 0.4
PSA = 130pKa = 4.1logD7.4 = 1.8
O
LeadKi ETA = 43 nM
O O
SB 209670Ki ETA = 0 4 nM
SB 217242Ki ETA = 1 1 nMA
Caco-2 cell permeabilityPapp = 0.17 cm/hr
Ki ETA 0.4 nMPapp = 0.0075 cm/hr< 5% bioavailable (rat)
Ki ETA 1.1 nMPapp = 0.2 cm/hr66% bioavailable
• Caco-2 cell assay used to identify issue with SB 209670 – low intestinal permeability and rapidly identify non acidic sides chains with improved permeabilityy y y y
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DistributionDistribution
And you thought getting And you thought getting from the gut to the blood was a challengewas a challenge…
BBBBBB
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Distribution to Site of ActionBl d B i B i d CNS P t tiBlood Brain Barrier and CNS Penetration
What is the BBB?at s t e• Blood Brain Barrier is the interface between blood vessels and brain cells
• Protective lipid membrane with tight cellular junctionsotect e p d e b a e t t g t ce u a ju ct o s
• Polar, hydrophilic molecules are prevented from entering CNS
• Active transport does operate eg for peptides, amino acids, glucose, fatty acidsp p g p p g y
• Efflux pumps (eg P-gp) acts to keep “foreign” drug molecules out of CNS
• BBB has some metabolic capacity
• Main route of CNS drug penetration is by passive diffusion
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Blood Brain Barrier PenetrationFeatures of CNS drugs
• Mol Weight < 400• Mol Weight < 400
• logP/ logD 2 – 4 (optimum ~ 2)Strong correlation of logD and passive permeability to BBB penetrationStrong correlation of logD and passive permeability to BBB penetration
• PSA < 60-90 Å2PSA range for 776 oral CNS drugs thatreached phase 2 efficacy studies
• pKa - optimum pKa range is 7.5 – 10.5
• H-bond donors 0 - 1
• Few CNS drugs are P-gp substrates - harder to achieve saturating concentrations in plasma.
Journal of Medicinal Chemistry, 2006, 49, 26, 7559
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5-HT6 Antagonists
NH
NH
NO
N
NO
NH
S SO
OS ClO
O
Cl
OSB-271046 5-HT6 pKi > 8.0
MW 452 390clogP 4.1 3.0clogD 3.6 1.4PSA (A2) 71 54PSA (A2) 71 54HBD 2 1Brain / Plasma 0.05 2.6
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Brain Teaser – 5-HT Receptor AgonistsBrain Teaser – 5-HT1D Receptor Agonists (J. Med. Chem. 1999, 42 2087 – 2104)
N
N
NN
NH
NPh
H
1
Compound 5-HT1D Ki pKa cLogD Concentration in rat plasmaCompound 5-HT1D Ki pKa cLogD Concentration in rat plasma HPV sampling 0.5h after 3 mg/kg p.o.
1 0.3 nM 9.7 2.5 25 ng/ ml
Compound 1 is a potent 5-HT1D agonist but is poorly absorbed orallyBasic Nitrogen is important to activity
What is a possible barrier to absorption?What strategies would you use to attempt to improve oral absorption?g y p p p
HPV = hepatic portal vein