Abstract: Lead Optimization And Drug Metabolism And Pharmacokinetics(dmpk) Has Become

Lead Optimization in Drug Discovery/DMPK

Case Study : Hepatitis C virus Protease Inhibitor SCH 503034

Abstract: Lead Optimization and drug metabolism and pharmacokinetics(DMPK) has become primary focuses of research involved in drug discovery. Using in vivo and in vitro DMPK screening, a large array of compounds during LO process has resulted in development of compounds that have acceptable DMPK properties. In this poster I present a general drug discovery process and a case study using HCV protease inhibitor as an example. Introduction: •Multifaceted Operation •Involves interaction between DMPK scientist, biologist and physical chemists. •Goal: to find molecule with desired Biological Activity, DMPK property and safety

Lead Generation as a part of new drug discovery: •Contemporary parallel and combinatorial chemical synthesis produce large arrays of compounds •Improvements by structural chemist using variety of tools, e.g. X-ray crystallography, High throughput binding targets •New automated in vitro Screening –can test 100’s of sample in short time. •Increase our ability to create New Chemical Entity(NCE) Lead optimization in a DMPK environment

Drug Metabolism As a Part of New Drug Discovery: Scheme shows: Nature of Property Potency lead optimization leading Oral Bioavailability to candidate •DMPK provides with tools Duration (Half-life) and the assay to assess Safety various NCE in terms of ADME and pharmacokinetic Pharmaceutical Acceptability parameters •Goal is to find a compound suitable for development

Case study: HCV protease Screening Paradigm

Method : Hepatitis C virus : •~170 million people infected with HCV •Chronic form of hepatitis •HCV servers a template for cap independent translation through its 5’ terminal. •3000amino acid undergo-co and post translational proteolytic maturation by host and virus. •Virus encoded protease located at NS3. •This effect targeting the E-S binding site resulted in SCH 503034 DMPK screening : Level 1 DMPK screening applied to HCV compound ~ METHOD •10,000compounds --- Replicon assay •1,000 met the criterion of IC90. 2 l • e v Le •1st level--- Screening with Caco2,CYP enzyme inhibition, liver uptake screening 3 l ve Le • •2nd level---More labor intensive assay, studies in H 4 rodent and non rodent SC 03 3 50 species. Screens – Caco2 permeability Screen , Human hepatocyte Clearance Screening , CYP enzyme inhibition screen , hPXR screen , Esterase / amidase stability screen , Rat liver uptake screen , Cassette - Accelerated Rapid rat screen

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Definition/Requirement The intrinsic ability of a compound to produce a desirable pharmacological response (usually measured via high throughput in vitro screens) The ability of a compound to pass through multiples barriers, such as the GI tract and the liver in order to reach the target The ability of the compound to remain in circulation (or at the target site) for sufficient time to provide a meaningful pharmacological response The compound has sufficient selectivity for the targeted response relative to non-targeted responses so that an adequate therapeutic index exists The compound has suitable pharmaceutical properties, such as a reasonable synthetic pathway, adequate aqueous solubility, reasonable rate of dissolution, good chemical stability, etc.

Result•moderate oral bioavailability in rats and dogs •Absence of reactive metabolite •IC50>5uM for CYPs3A4, 2D6, 2C8 and 2C9 •Moderate huan Hepatocyte clearance •No CYP induction liability

Macrocyclic Compounds: SCH 416538, resistance to peptidases and amidases, Better potency. Secondary Amides: SCH 446211,reasonable half life, potential dosage regimen. Primary Ketoamides: SCH 503034 met criteria for this program and was advanced into development.

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Conclusion: DMPK screens and new techniques have become an essential part of drug discovery process. There is continuous need to improve predictions by using in vitro evaluations. Future: It may become possible to use in silico DMPK computer model parameters to support the rapid screening of drugs to shorten the time frame of lead optimization.

•Out of 1000, 3 were advanced leads with SCH503034 Reference: •K.-C. Cheng1, Walter A. Korfmacher1, Ronald E. White1 •A few advanced leads were identified that had and F. George Njoroge2 acceptable DMPK characteristics. 1Department of Drug Metabolism and Pharmacokinetics . • 2Chemistry Department Schering-Plough •It went through a DMPK profiling process for the Research Institute, 2015 Galloping Hill Road, final selection of the best compound for drug Kenilworth, NJ 07033 USA. development (3rd level).