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

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

Author information

1
Department of Medicinal Chemistry, Gilead Sciences, Foster City, CA, USA. Electronic address: hongtao.liu@gilead.com.
2
Department of Medicinal Chemistry, Gilead Sciences, Foster City, CA, USA.
3
Department of Biology, Gilead Sciences, Foster City, CA, USA.
4
Department of Drug Metabolism, Gilead Sciences, Foster City, CA, USA.
5
Department of Structural Chemistry, Gilead Sciences, Foster City, CA, USA.

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

PMID:
24411125
DOI:
10.1016/j.bmcl.2013.12.058
[Indexed for MEDLINE]

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