(3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1h-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic acid (BMS-644950): a rationally designed orally efficacious 3-hydroxy-3-methylglutaryl coenzyme-a reductase inhibitor with reduced myotoxicity potential

Journal of Medicinal Chemistry
Saleem AhmadJeffrey A Robl

Abstract

3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.

References

Jan 1, 1988·Experimental Pathology·P RebuffatG G Nussdorfer
Apr 4, 1986·Science·M S Brown, J L Goldstein
Aug 1, 1971·Lipids·D M Capuzzi, S Margolis
Jul 1, 1980·Proceedings of the National Academy of Sciences of the United States of America·A W AlbertsJ Springer
Aug 17, 1999·Archives of Internal Medicine·S D RossD Luo
May 5, 2001·Expert Opinion on Pharmacotherapy·A S Wierzbicki
May 12, 2001·Science·E S Istvan, J Deisenhofer
Sep 28, 2001·The Annals of Pharmacotherapy·M A OmarT S Cox
Oct 16, 2001·European Journal of Clinical Pharmacology·M IgelK von Bergmann
Jan 5, 2002·The Medical Journal of Australia·I Hamilton-Craig
Jan 5, 2002·Expert Opinion on Investigational Drugs·Michael H Davidson
Jul 26, 2002·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Marc Evans, Alan Rees
Aug 31, 2002·Rapid Communications in Mass Spectrometry : RCM·Yining ZhaoEd Maliski
Oct 19, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ken-ichi NezasaMasahiro Koike
Mar 8, 2003·Archives of Internal Medicine·Christie M BallantyneEvan A Stein
Apr 4, 2003·JAMA : the Journal of the American Medical Association·Paul D ThompsonRichard H Karas
May 15, 2003·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·K NezasaM Koike
Nov 26, 2003·The American Journal of Cardiology·Evan A SteinUNKNOWN HeFH Study Group
Jan 22, 2005·Fundamental & Clinical Pharmacology·Michael Schachter
Nov 25, 2005·Arteriosclerosis, Thrombosis, and Vascular Biology·M John Chapman, Alain Carrie
Aug 8, 2006·Journal of Cardiovascular Pharmacology and Therapeutics·Rohit AroraFrank Maldonado
Jun 15, 2007·Lancet·Jane Armitage
Jun 19, 2007·Bioorganic & Medicinal Chemistry Letters·Jeffrey A PfefferkornMatthias Eberstadt
Nov 8, 2007·The Journal of Pharmacology and Experimental Therapeutics·Cort S MadsenPhilip D Stein

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Citations

Jun 1, 2009·Future Medicinal Chemistry·Adrian Hall
Nov 1, 2009·Future Medicinal Chemistry·David J Newman, Gordon M Cragg
Mar 14, 2014·Cardiovascular Research·Emil KozarovLina Badimon
Aug 15, 2009·Current Opinion in Neurology·Ralph W Kuncl
Jan 11, 2011·Expert Opinion on Therapeutic Patents·Jeffrey A Pfefferkorn
Oct 12, 2010·Bioorganic & Medicinal Chemistry Letters·Koneni V SashidharaAnju Puri
Sep 17, 2009·Current Opinion in Neurology

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