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

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).

Author information

  • 1Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA. Electronic address: lianhong.xu@gilead.com.
  • 2Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
  • 3Department of Drug Metabolism, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
  • 4Department of Biology, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
  • 5Department of Formulation, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
  • 6Department of Structural Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.

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.

Copyright © 2013 Elsevier Ltd. All rights reserved.

KEYWORDS:

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

[PubMed - indexed for MEDLINE]
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