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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
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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.
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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
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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