title: (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.
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.
authors.affiliation: Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, USA. saleem.ahmad@bms.com
authors.forename: Saleem
authors.initials: S
authors.lastname: Ahmad
authors.forename: Cort S
authors.initials: CS
authors.lastname: Madsen
authors.forename: Philip D
authors.initials: PD
authors.lastname: Stein
authors.forename: Evan
authors.initials: E
authors.lastname: Janovitz
authors.forename: Christine
authors.initials: C
authors.lastname: Huang
authors.forename: Khehyong
authors.initials: K
authors.lastname: Ngu
authors.forename: Sharon
authors.initials: S
authors.lastname: Bisaha
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Kennedy
authors.forename: Bang-Chi
authors.initials: BC
authors.lastname: Chen
authors.forename: Rulin
authors.initials: R
authors.lastname: Zhao
authors.forename: Doree
authors.initials: D
authors.lastname: Sitkoff
authors.forename: Hossain
authors.initials: H
authors.lastname: Monshizadegan
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yin
authors.forename: Carol S
authors.initials: CS
authors.lastname: Ryan
authors.forename: Rongan
authors.initials: R
authors.lastname: Zhang
authors.forename: Mary
authors.initials: M
authors.lastname: Giancarli
authors.forename: Eileen
authors.initials: E
authors.lastname: Bird
authors.forename: Ming
authors.initials: M
authors.lastname: Chang
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.forename: Robert
authors.initials: R
authors.lastname: Setters
authors.forename: Debra
authors.initials: D
authors.lastname: Search
authors.forename: Shaobin
authors.initials: S
authors.lastname: Zhuang
authors.forename: Van
authors.initials: V
authors.lastname: Nguyen-Tran
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Cuff
authors.forename: Thomas
authors.initials: T
authors.lastname: Harrity
authors.forename: Celia J
authors.initials: CJ
authors.lastname: Darienzo
authors.forename: Tong
authors.initials: T
authors.lastname: Li
authors.forename: Richard A
authors.initials: RA
authors.lastname: Reeves
authors.forename: Michael A
authors.initials: MA
authors.lastname: Blanar
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: Robert
authors.initials: R
authors.lastname: Zahler
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood; D018360:Crystallography, X-Ray; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D000882:Haplorhini; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity
chemical_list: C529816:7-(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; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases