Structure-activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers. Part II: P2/P3 region and discovery of cobicistat (GS-9350)

Bioorg Med Chem Lett. 2014 Feb 1;24(3):995-9. doi: 10.1016/j.bmcl.2013.12.057. Epub 2013 Dec 21.

Abstract

The HIV protease inhibitor (PI) ritonavir (RTV) has been widely used as a pharmacoenhancer for other PIs, which are substrates of cytochrome P450 3A (CYP3A). However the potent anti-HIV activity of ritonavir may limit its use as a pharmacoenhancer with other classes of anti-HIV agents. Ritonavir is also associated with limitations such as poor physicochemical properties. To address these issues a series of compounds with replacements at the P2 and/or P3 region was designed and evaluated as novel CYP3A inhibitors. Through these efforts, a potent and selective inhibitor of CYP3A, GS-9350 (cobicistat) with improved physiochemical properties was discovered.

Keywords: 1,4-Diamines; CYP3A inhibitors; Pharmacoenhancer; Selectivity against different CYP enzymes.

MeSH terms

  • Carbamates / chemistry*
  • Carbamates / pharmacology
  • Cobicistat
  • Cytochrome P-450 CYP3A Inhibitors*
  • Diamines / chemistry*
  • Diamines / pharmacology*
  • Enzyme Activation / drug effects
  • Molecular Structure
  • Structure-Activity Relationship
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology

Substances

  • Carbamates
  • Cytochrome P-450 CYP3A Inhibitors
  • Diamines
  • Thiazoles
  • Cobicistat