Structure-activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers, part I: core region

Bioorg Med Chem Lett. 2014 Feb 1;24(3):989-94. doi: 10.1016/j.bmcl.2013.12.058. Epub 2013 Dec 19.

Abstract

Ritonavir (RTV), an HIV-1 protease inhibitor (PI), is also a potent mechanism-based inhibitor of human cytochrome P450 3A (CYP3A) and has been widely prescribed as a pharmacoenhancer. As a boosting agent for marketed PIs, it reduces pill burden, and improves compliance. Removal of the hydroxyl group from RTV reduces, but does not eliminate HIV PI activity and does not affect CYP3A inhibition. Herein we report the discovery of a novel series of CYP3A inhibitors that are devoid of antiviral activity. The synthesis and evaluation of analogs with extensive modifications of the 1,4-diamine core along with the structure activity relationships with respect to anti-HIV activity, CYP3A inhibitory activity, selectivity against other CYP enzymes and the human pregnane X receptor (PXR) will be discussed.

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

MeSH terms

  • Cytochrome P-450 CYP3A Inhibitors*
  • Diamines / chemical synthesis*
  • Diamines / chemistry
  • Diamines / pharmacology*
  • Enzyme Activation / drug effects
  • HIV / drug effects*
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology
  • Humans
  • Structure-Activity Relationship
  • Treatment Outcome

Substances

  • Cytochrome P-450 CYP3A Inhibitors
  • Diamines
  • HIV Protease Inhibitors