Design, synthesis, and structure-activity relationships of unsubstituted piperazinone-based transition state factor Xa inhibitors

Wenrong Huang; Mary Ann Naughton; Hua Yang; Ting Su; Suiko Dam; Paul W Wong; Ann Arfsten; Susan Edwards; Uma Sinha; Stanley Hollenbach; Robert M Scarborough; Bing-Yan Zhu

doi:10.1016/s0960-894x(02)01037-5

Design, synthesis, and structure-activity relationships of unsubstituted piperazinone-based transition state factor Xa inhibitors

Bioorg Med Chem Lett. 2003 Feb 24;13(4):723-8. doi: 10.1016/s0960-894x(02)01037-5.

Authors

Wenrong Huang¹, Mary Ann Naughton, Hua Yang, Ting Su, Suiko Dam, Paul W Wong, Ann Arfsten, Susan Edwards, Uma Sinha, Stanley Hollenbach, Robert M Scarborough, Bing-Yan Zhu

Affiliation

¹ Department of Medicinal Chemistry, Millennium Pharmaceuticals Inc., 256 East Grand Ave., South San Francisco, CA 94080, USA.

PMID: 12639567
DOI: 10.1016/s0960-894x(02)01037-5

Abstract

A series of novel transition state factor Xa inhibitors containing a variety of lactam ring systems as central templates was synthesized in an expedient manner and allowed for a great deal of structural variability. Among them, the piperazinone-based inhibitors were found to be not only active against factor Xa but also selective over thrombin. Optimization of the P4 moiety yielded several potent compounds with IC(50) below 1 nM against factor Xa.

MeSH terms

Animals
Anticoagulants / chemical synthesis
Anticoagulants / pharmacokinetics
Blood Coagulation Tests
Drug Design
Drug Evaluation, Preclinical
Factor Xa Inhibitors*
Humans
Inhibitory Concentration 50
Piperazines / chemical synthesis*
Piperazines / pharmacokinetics*
Piperazines / pharmacology
Rabbits
Rats
Rats, Sprague-Dawley
Serine Proteinase Inhibitors / chemical synthesis*
Serine Proteinase Inhibitors / pharmacokinetics
Serine Proteinase Inhibitors / pharmacology
Structure-Activity Relationship
Thrombosis / prevention & control

Substances

Anticoagulants
Factor Xa Inhibitors
Piperazines
Serine Proteinase Inhibitors