PMID: 11899249Mar 20, 2002Paper

The design and synthesis of noncovalent factor Xa inhibitors

Current Topics in Medicinal Chemistry
M L Quan, R R Wexler

Abstract

Thrombosis is a major cause of mortality in the industrialized world. Therefore, the control of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (fXa), the enzyme directly responsible for thrombin generation. In this review we describe our approaches in the design and synthesis of small molecule, noncovalent fXa inhibitors. Rational drug design and selective screening of our GPIIb/IIIa library afforded several lead compounds for our fXa program. Following-up the leads in the isoxazoline series led to potent fXa inhibitors such as SF303 and SK509 with only one basic group. The isoxazole series was then designed to remove the chiral center in the isoxazoline ring, and this effort led to SA862 which has subnanomolar fXa affinity. Optimizing the core structure generated a series of novel five-membered ring heterocycles substituted with benzamidine, which are potent fXa inhibitors. Further optimization in the pyrazole series resulted in the discovery of fXa inhibitors such as SN429 with picomolar fXa affinity. Efforts to improve the oral bioavailability by lowering the basicity of these compounds, while simultaneously maintaining potency against fXa, culmi...Continue Reading

Citations

Apr 5, 2011·European Journal of Drug Metabolism and Pharmacokinetics·Kan HeScott J Grossman
Aug 23, 2003·Journal of Molecular Graphics & Modelling·Yasunobu TakanoTohru Koike
Mar 6, 2010·International Journal of Obstetric Anesthesia·A J Butwick, B Carvalho
Dec 3, 2008·Bioorganic & Medicinal Chemistry Letters·Jennifer X QiaoPatrick Y S Lam
May 30, 2007·Biochemical and Biophysical Research Communications·Lanying DuBo-Jian Zheng
Jul 8, 2015·Journal of Medicinal Chemistry·E Scott PriestleyRuth R Wexler
May 1, 2010·Biochimie·Neil D Rawlings
Jan 27, 2004·The Annals of Pharmacotherapy·Edith A Nutescu, Ann K Wittkowsky
Nov 20, 2002·The Journal of Pharmacology and Experimental Therapeutics·Pancras C WongRobert M Knabb
Jun 22, 2016·Microbial Drug Resistance : MDR : Mechanisms, Epidemiology, and Disease·Ivanna RiveraJuan A Hermoso
Feb 5, 2003·Bioorganic & Medicinal Chemistry Letters·Mimi L QuanRuth R Wexler
Mar 20, 2003·Bioorganic & Medicinal Chemistry Letters·Mimi L QuanRuth R Wexler

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