Discovery of novel hepatoselective HMG-CoA reductase inhibitors for treating hypercholesterolemia: a bench-to-bedside case study on tissue selective drug distribution

Bioorg Med Chem Lett. 2011 May 1;21(9):2725-31. doi: 10.1016/j.bmcl.2010.11.103. Epub 2010 Nov 26.

Abstract

The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.

MeSH terms

  • Animals
  • Cells, Cultured
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Hepatocytes / drug effects
  • Heptanoic Acids / chemical synthesis*
  • Heptanoic Acids / chemistry
  • Heptanoic Acids / pharmacokinetics
  • Heptanoic Acids / pharmacology
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / chemical synthesis*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Hypercholesterolemia / drug therapy*
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology
  • Inhibitory Concentration 50
  • Liver / drug effects*
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology
  • Rats
  • Tissue Distribution

Substances

  • 7-(2-(4-fluorophenyl)-4-isopropyl-5-(4-methylbenzylcarbamoyl)-2H-pyrazol-3-yl)-3,5-dihydroxyheptanoic acid
  • 7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Imidazoles
  • Pyrazoles