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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 Few research compounds will become drugs because they lack sufficient pharmacokinetics (PK) and safety 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 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 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 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 (25g/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: Increase lipophilicity Reduce molecular weight Reduce rotatable bonds Prodrug O N H H N O O N H H N O 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