The role of exploratory drug metabolism and pharmacokinetics in new drug research: case study-selection of a thrombin receptor antagonist for development.
The rising costs and time associated with bringing new medicines to the market have created a need for a new paradigm for reducing the attrition rates of drug candidates in both preclinical and clinical development stages. Early appraisal of drug metabolism and pharmacokinetic (DMPK) parameters is now possible due to several higher throughput in vitro and in vivo screens. This knowledge of DMPK properties should not only shorten the timelines for the selection of drug candidates but also enhance the probability of their success for development. The role of DMPK researchers in the drug research paradigm should not be limited to screening a large array of compounds during the lead optimization process but should include a strive for an understanding of the absorption, distribution, metabolism, excretion, and potential drug-related toxicities of a chemical series. As an example, in this article we present a specific DMPK research screening paradigm and describe a case study using the Thrombin Receptor Antagonist program. This screening paradigm followed by the extensive lead optimization process culminated in the selection of SCH 530348, a potent, selective and orally active thrombin receptor antagonist for the treatment of thrombosis.
Hsieh
Yunsheng
Y
Department of Drug Metabolism and Pharmacokinetics and Department of Medicinal Chemistry; Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. yunsheng.hsieh@spcorp.com
Cheng
K-C
KC
Wang
Yuguang
Y
Chackalamannil
Samuel
S
Xia
Yan
Y
Korfmacher
Walter A
WA
White
Ronald E
RE
D000818:Animals; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004345:Drug Industry / Q000191:economics / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007783:Lactones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000188:drug therapy / Q000503:physiopathology
D007783:Lactones; D004364:Pharmaceutical Preparations; D011725:Pyridines; D018179:Receptors, Thrombin; C530299:vorapaxar