Design and synthesis of novel, conformationally restricted HMG-CoA reductase inhibitors.
Using structure-based design, a novel series of conformationally restricted, pyrrole-based inhibitors of HMG-CoA reductase were discovered. Leading analogs demonstrated potent inhibition of cholesterol synthesis in both in vitro and in vivo models and may be useful for the treatment of hypercholesterolemia and related lipid disorders.
Pfefferkorn
Jeffrey A
JA
Pfizer Global Research & Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. jeffrey.a.pfefferkorn@pfizer.com
Choi
Chulho
C
Song
Yuntao
Y
Trivedi
Bharat K
BK
Larsen
Scott D
SD
Askew
Valerie
V
Dillon
Lisa
L
Hanselman
Jeffrey C
JC
Lin
Zhiwu
Z
Lu
Gina
G
Robertson
Andrew
A
Sekerke
Catherine
C
Auerbach
Bruce
B
Pavlovsky
Alexander
A
Harris
Melissa S
MS
Bainbridge
Graeme
G
Caspers
Nicole
N
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D015195:Drug Design; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000188:drug therapy; D051379:Mice; D008967:Molecular Biology; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D002784:Cholesterol