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

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 activation of the human pregnane X receptor (PXR) will...

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Published in:	Bioorganic & medicinal chemistry letters 2014-02, Vol.24 (3), p.989-994
Main Authors:	Liu, Hongtao, Xu, Lianhong, Hui, Hon, Vivian, Randy, Callebaut, Christian, Murray, Bernard P., Hong, Allen, Lee, Melody S., Tsai, Luong K., Chau, Jennifer K., Stray, Kirsten M., Cannizzaro, Carina, Choi, You-Chul, Rhodes, Gerry R., Desai, Manoj C.
Format:	Article
Language:	eng
Subjects:	1,4-Diamines CYP3A inhibitors 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 HIV-1 protease inhibitors Human immunodeficiency virus Human immunodeficiency virus 1 Humans Pharmacoenhancer Selectivity against different CYP enzymes Structure-Activity Relationship Treatment Outcome
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Summary:	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 activation of the human pregnane X receptor (PXR) will be discussed. 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.
ISSN:	0960-894X 1464-3405