Substituted pyrazoles as hepatoselective HMG-CoA reductase inhibitors: discovery of (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxyheptanoic acid (PF-3052334) as a candidate for the treatment of hypercholesterolemia.
In light of accumulating evidence that aggressive LDL-lowering therapy may offer increased protection against coronary heart disease, we undertook the design and synthesis of a novel series of HMG-CoA reductase inhibitors based upon a substituted pyrazole template. Optimizing this series using both structure-based design and molecular property considerations afforded a class of highly efficacious and hepatoselective inhibitors resulting in the identification of (3 R,5 R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2 H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic (PF-3052334) as a candidate for the treatment of hypercholesterolemia.
Pfefferkorn
Jeffrey A
JA
Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. jeffrey.a.pfefferkorn@pfizer.com
Choi
Chulho
C
Larsen
Scott D
SD
Auerbach
Bruce
B
Hutchings
Richard
R
Park
William
W
Askew
Valerie
V
Dillon
Lisa
L
Hanselman
Jeffrey C
JC
Lin
Zhiwu
Z
Lu
Gina H
GH
Robertson
Andrew
A
Sekerke
Catherine
C
Harris
Melissa S
MS
Pavlovsky
Alexander
A
Bainbridge
Graeme
G
Caspers
Nicole
N
Kowala
Mark
M
Tait
Bradley D
BD
D000818:Animals; D008078:Cholesterol, LDL / Q000096:biosynthesis / Q000097:blood; D006224:Cricetinae; D006168:Guinea Pigs; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006538:Heptanoic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000188:drug therapy*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C526799:7-(2-(4-fluorophenyl)-4-isopropyl-5-(4-methylbenzylcarbamoyl)-2H-pyrazol-3-yl)-3,5-dihydroxyheptanoic acid; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011720:Pyrazoles