title: 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.
abstract: 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.
authors: Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. jeffrey.a.pfefferkorn@pfizer.com
authors: Jeffrey A
authors: JA
authors: Pfefferkorn
authors: Chulho
authors: C
authors: Choi
authors: Scott D
authors: SD
authors: Larsen
authors: Bruce
authors: B
authors: Auerbach
authors: Richard
authors: R
authors: Hutchings
authors: William
authors: W
authors: Park
authors: Valerie
authors: V
authors: Askew
authors: Lisa
authors: L
authors: Dillon
authors: Jeffrey C
authors: JC
authors: Hanselman
authors: Zhiwu
authors: Z
authors: Lin
authors: Gina H
authors: GH
authors: Lu
authors: Andrew
authors: A
authors: Robertson
authors: Catherine
authors: C
authors: Sekerke
authors: Melissa S
authors: MS
authors: Harris
authors: Alexander
authors: A
authors: Pavlovsky
authors: Graeme
authors: G
authors: Bainbridge
authors: Nicole
authors: N
authors: Caspers
authors: Mark
authors: M
authors: Kowala
authors: Bradley D
authors: BD
authors: Tait
mesh_terms: 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
chemical_list: 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