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

  • J Med Chem. 2008 Jan 10;51(1):31-45. doi: 10.1021/jm070849r.
Jeffrey A Pfefferkorn  1 ,  Chulho Choi ,  Scott D Larsen ,  Bruce Auerbach ,  Richard Hutchings ,  William Park ,  Valerie Askew ,  Lisa Dillon ,  Jeffrey C Hanselman ,  Zhiwu Lin ,  Gina H Lu ,  Andrew Robertson ,  Catherine Sekerke ,  Melissa S Harris ,  Alexander Pavlovsky ,  Graeme Bainbridge ,  Nicole Caspers ,  Mark Kowala ,  Bradley D Tait
Affiliations
  • 1. Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. [email protected]
PMID: 18072721 DOI: 10.1021/jm070849r
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.