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Drug-Like Properties:
Optimizing Pharmacokinetics and
Safety During Drug Discovery
Li Di and Edward H. Kerns
ACS Short Course
Introduction to Drug-Like Properties
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Few research compounds will become drugs because
they lack sufficient pharmacokinetics (PK) and safety
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Medicinal chemists strive to:
1. Deliver drug to the therapeutic target in sufficient concentration and time (PK)
2. Eliminate toxicity at the efficacious dose (safety)
3. Bind drug productively to the therapeutic target
4. Produce therapeutic efficacy in vivo
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This course increases success in selecting and
optimizing clinical candidates for good PK and safety
There are Many Manifestations of Poor Properties
During Drug Discovery
• Higher EC50 in cell assay than predicted from IC50
• Inadequate efficacy in animal model
• Poor brain penetration
• Low oral bioavailability
• Need a prodrug for absorption
• Inconsistent bioassay results
Short Course Format
Property
Fundamentals
Property
Effects
Med-Chem
Literature Case
Studies
Chemist
Structure Modification
Strategies
Lead
- with
Liabilities
Candidate
- with
Improved
PK
Course Overview
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Solubility
Metabolic stability
Permeability
Transporters (efflux and uptake)
Blood-Brain barrier
Plasma protein binding
Lipophilicity
pKa
Plasma stability
In vivo barriers to drug exposure
Introduction to pharmacokinetics and toxicity
Diagnosing property liabilities
CYP Inhibition
hERG
Formulation for in vivo dosing
Group exercises
Q & A encouraged
Example:
PERMEABILITY
Example: Permeability Fundamentals
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Rate of compound flux through a lipid
membrane barrier
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When is permeability important ?
Absorption – Intestine (orally delivered drugs)
Organ barriers (e.g., BBB)
Cells – In vivo tissue with target
Cells – In vitro biological assay
Example: Permeation Fundamentals
Permeation Mechanisms:
P: Passive Diffusion***
P
F
A
D
E
E: Efflux (Transporters)
e.g., P-glycoprotein
Epithelial
Cell
A: Active Uptake
(Transporters)
F: Facilitated Uptake
D: Paracellular
95% of commercial drugs are primarily absorbed by passive diffusion
Example: Effects of Improved Permeability
• Increased bioavailability
• Improved cell assay results
• Higher blood-brain barrier penetration
• Targeting of drugs to specific tissues
• Reduced clearance
Example: Permeability Assay – PAMPA
Acceptor
Buffer (pH 7.4)
Artificial Lipid
Membrane
Donor
Drug in Buffer
(25g/mL, pH 7.4)
Measure “Pe” (Effective Permeability) via Passive Diffusion
M. Kansy, J Med Chem (1998) 41, 1007
Structural Modifications to Improve Permeability
Examples:
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Increase lipophilicity
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Reduce molecular weight
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Reduce rotatable bonds
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Prodrug
O
N
H
H
N
O
O
N
H
H
N
O
Advantages of Quality Drug-Like Properties
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Higher quality clinical candidates
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Advantageous partnering opportunities
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Candidates have lower failure risk
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Reduced time lag to fix PK liabilities later
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Faster & less expensive development
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Higher patient compliance
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Better discovery biology data
Instructors
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Dr. Li Di – Associate Research Fellow, Pharmacokinetics,
Dynamics and Metabolism, Pfizer Research
Over 20 years in drug discovery and development
Over 120 research publications and invited lectures
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Edward H. Kerns – Staff Scientist, NIH – NCATS
Over 30 years in drug discovery and development
Over 120 research publications and invited lectures
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Co-authors of a leading book: “Drug-like
Properties: Concepts, Structure Design and
Methods”
Presented course over 25 times in 6 years