Advanced Chemistry Development, Inc. (ACD/Labs)

www.acdlabs.comwww.acdlabs.com

Easier and Better Exploitation of PhysChem

Properties in Medicinal Chemistry

Dr. Sanjivanjit K. Bhal

2

Evolution of MedChem

<1980 target affinity/binding using intuition and experience

>1980 structure-based design

>1995 drug/lead filters such as Rule-of-5

>2000 property-based design

>2005 in-silico/in-vitro (in combination)

protein crystallography

attrition analyses

physchem/DMPK considerations

HT property screening

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The Challenge of MedChem

To convert a molecule that shows good activity towards a

therapeutic target, into a drug.

4

Overcoming the Challenge

Physicochemical properties govern the passive transport of compounds through the body. We must:

Understand how these properties influence drugabilityFocus on property optimization

5

Overview

Relate physical properties with compound ‘drugability’

Key influences in application of PhysChem properties

Discuss how individual properties effect in-vivo behavior

Effective application of PhysChem data

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ADME related Lead OptimizationADME related Lead Optimization

Poor Systemic ExposurePoor Systemic Exposure

ClearanceClearance

Poor Oral BioavailabilityPoor Oral Bioavailability

AbsorptionAbsorption(permeation)(permeation)

DistributionDistribution First Pass ClearanceFirst Pass Clearance

Carlson and Segall, Curr.Drug Disc., 2002, 34-36.

pKpKaa SolubilitySolubility LogLogPP/Log/LogDD

PhysChem Properties Relate Directly to Endpoints

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PhysChem Properties Relate Directly to Endpoints

Select parameters affected by PhysChem properties

Blood brain barrier permeabilityTissue partitioningProtein bindingPermeabilityBioavailability

EfficacyPhysical

PropertiesADME

Toxicity

Selectivity

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Key Influences—Oral Bioavailability

Veber1

C. Lipinski—Rule-of-52

MWt <500 <5 H-bond donor atomsLogP <5Sum of H-bond acceptors <10

1. Veber, J. Med Chem., 45, 2615-26232. C. A. Lipinski, F. Lombardo, B. W. Dominey, P.J. Feeney, Drug Del. Rev., 1997,

23, 3-25.

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Key Influences—Permeability

Hansch—Rule of thumb for blood brain barrier permeability logP ~2

Clarke—Published equation for BBB prediction using PhysChem factors1

LogBB=(-0.0148 × PSA)+ (0.152 × ClogP) + 0.139

1. D. E. Clarke, J. Pharm. Sci., 88, 1999, 815–821.2. G. M. Rishton, K. LaBonte, A. J. Williams, K. Kassam, E. Kolovanov, Curr. Opin. Drug Disc. & Dev.; 2006; 9, (3), 303-313.

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ACD/Labs PhysChem Challenge

5 PhysChem questions <1% participants got 6/6

Conclusions from results:It is difficult to see trends in structurally dissimilar compoundsWe don’t necessarily know how to relate PhysChem data with structural modification

www.acdlabs.com/physchem_quiz/www.acdlabs.com/physchem_quiz/

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Lipophilicity (logP/logD)

LogP-neutral compounds LogD-ionizable compounds

pH

% Species

7 14

100.00

66.67

0.00

LHL

H2LH3L

pH

LogD

7 14

0.59

-0.42

-2.43-2.43

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LogP vs. LogD

AspirinAspirin

LogD ProfileLogD Profile

Speciation Speciation DiagramDiagram

logPlogP

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LogP vs. LogD

LogD Profile of Salicylic Acid (active ingredient) LogD Profile of Salicylic Acid (active ingredient)

LogD Profile of Aspirin (ProLogD Profile of Aspirin (Pro--Drug) Drug)

logPlogP

logPlogP

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Impact of Modifying LogPCase Study

2-(2-dimethoxyphenyl)-1H-imidazo[4,5-b]pyridine

LogLogPP 2.592.59Lead cardiotonic agent showing CNS activity Lead cardiotonic agent showing CNS activity

SulmazoleLogLogPP 1.171.17Final DrugFinal Drug

No CNS sideNo CNS side--effectseffects

E. Kutter & V. Austel, Arzneim.-Forsch., 1981, 31, 135.

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Ionization (pKa)

Which pKWhich pKaa is physiologically relevant?is physiologically relevant?

pKa 4.4 15.3, 9.9, 1.7 10.9, 4.7

O

OH

CH3

CH3

CH3

NH

OOH

CH3N

OCH3

CH3

NH

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Aqueous Solubility

930.251.3Vioxx

830.081.7Bextra

400.014.2Celebrex

Bioavailability(%)

Solubility (mg/mL)LogPNSAID

S

O

O

NH2

NN

CH3

F

F

F

O

NS NH2

O

OCH3

O

O

S

O

O

CH3

Celebrex Bextra Vioxx

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Full PhysChem Profile of Aspirin

ACD/LogD Sol Suite: www.acdlabs.com/logdsuite/

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Applying PhysChem Information in Medicinal Chemistry

pKpKaa

SolubilitySolubility

LogLogPP

LogLogDD

Compound XCompound X

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ACD/Structure Design Suite (SDS)

Purpose—suggest substituents to adjust PhysChem properties of parent structures in desired direction

LogPpKa (“single”)LogD (at selected pH)Solubility (at selected pH)

Easier Exploitation of PhysChem Properties

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ACD/Structure Design Suite

CH3

NHNH

N

N O

O

O

S

RCH3

NHNH

N

N O

O

O

S

SubstituentSubstituentDatabaseDatabase

OPTIMIZEOPTIMIZE

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Sulmazole Case Study

N

NH

O

NO

CH3

CH3

N

NH

S

N

O

O

CH3

CH3

SulmazoleLogLogPP 1.171.17

2-(2-dimethoxyphenyl)-1H-imidazo[4,5b]pyridine

Experimental LogExperimental LogPP 2.59 (ACD/Log2.59 (ACD/LogPP 2.47)2.47)

E. Kutter & V. Austel, Arzneim.-Forsch., 1981, 31, 135.

Cardiotonic agentSide effect-CNS activity

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Sulmazole Case Study

Goal: Optimize parent compound by reducing logP

Method: Property directed replacement of methoxy group

Conditions: Retain same number of freely rotatable bonds as parent

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Easier Exploitation of PhysChem Properties

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Take-home Message

Property-based design is best practiceUnderstanding the influence of PhysChem properties is pivotal to understanding ADMETo effectively apply PhysChem information we must:

Understand their influence Relate PhysChem Properties to structural modificationAchieve a balanced property profile

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Acknowledgements

Greg PearlEd KolovanovKarim Kassam

Ian Peirson

Further Reading:Further Reading:

‘Absorption & Drug Development: Solubility,Permeability and Charge State’—A. Avdeef