Drug-Like Properties: Optimizing Pharmacokinetics and Safety During Drug Discovery

Drug-Like Properties: Optimizing Pharmacokinetics and Safety During Drug Discovery Li Di and Edward H. Kerns ACS Short Course

Introduction to Drug-Like Properties • Few research compounds will become drugs because they lack sufficient pharmacokinetics (PK) and safety • Medicinal chemists strive to: • Deliver drug to the therapeutic target in sufficient concentration and time (PK) • Eliminate toxicity at the efficacious dose (safety) • Bind drug productively to the therapeutic target • Produce therapeutic efficacy in vivo • 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 • Poorbrain penetration • Low oral bioavailability • Need a prodrug for absorption • Inconsistent bioassay results

Property Effects Med-Chem Literature Case Studies Property Fundamentals Structure Modification Strategies Short Course Format Chemist Lead - with Liabilities • Candidate • with Improved PK

Course Overview • 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 • Rate of compound flux through a lipid membrane barrier • 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

P: Passive Diffusion*** D P F A E E: Efflux (Transporters) e.g., P-glycoprotein A: Active Uptake (Transporters) F: Facilitated Uptake D:Paracellular Example: Permeation Fundamentals Permeation Mechanisms: Epithelial Cell 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 Drug in Buffer (25g/mL, pH 7.4) Donor Measure “Pe” (Effective Permeability) via Passive Diffusion M. Kansy, J Med Chem(1998) 41, 1007

Structural Modifications to Improve Permeability Examples: • Increase lipophilicity • Reduce molecular weight • Reduce rotatable bonds • Prodrug

Advantages of Quality Drug-Like Properties • Higher quality clinical candidates • Advantageous partnering opportunities • Candidates have lower failure risk • Reduced time lag to fix PK liabilities later • Faster & less expensive development • Higher patient compliance • Better discovery biology data

Instructors • 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 • Edward H. Kerns – Staff Scientist, NIH – NCATS • Over 30 years in drug discovery and development • Over 120 research publications and invited lectures • Co-authors of a leading book: “Drug-like Properties: Concepts, Structure Design and Methods” • Presented course over 25 times in 6 years

Drug-Like Properties: Optimizing Pharmacokinetics and Safety During Drug Discovery