(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.
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.
Ahmad
Saleem
S
Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, USA. saleem.ahmad@bms.com
Madsen
Cort S
CS
Stein
Philip D
PD
Janovitz
Evan
E
Huang
Christine
C
Ngu
Khehyong
K
Bisaha
Sharon
S
Kennedy
Lawrence J
LJ
Chen
Bang-Chi
BC
Zhao
Rulin
R
Sitkoff
Doree
D
Monshizadegan
Hossain
H
Yin
Xiaohong
X
Ryan
Carol S
CS
Zhang
Rongan
R
Giancarli
Mary
M
Bird
Eileen
E
Chang
Ming
M
Chen
Xing
X
Setters
Robert
R
Search
Debra
D
Zhuang
Shaobin
S
Nguyen-Tran
Van
V
Cuff
Carolyn A
CA
Harrity
Thomas
T
Darienzo
Celia J
CJ
Li
Tong
T
Reeves
Richard A
RA
Blanar
Michael A
MA
Barrish
Joel C
JC
Zahler
Robert
R
Robl
Jeffrey A
JA
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
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