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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.

Authors
  • Pfefferkorn, Jeffrey A
  • Choi, Chulho
  • Larsen, Scott D
  • Auerbach, Bruce
  • Hutchings, Richard
  • Park, William
  • Askew, Valerie
  • Dillon, Lisa
  • Hanselman, Jeffrey C
  • Lin, Zhiwu
  • Lu, Gina H
  • Robertson, Andrew
  • Sekerke, Catherine
  • Harris, Melissa S
  • Pavlovsky, Alexander
  • Bainbridge, Graeme
  • Caspers, Nicole
  • Kowala, Mark
  • Tait, Bradley D
Type
Published Article
Journal
Journal of medicinal chemistry
Publication Date
Jan 10, 2008
Volume
51
Issue
1
Pages
31–45
Identifiers
PMID: 18072721
Source
Medline
License
Unknown

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.

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