Synthesis, biological activity, and ADME properties of novel S-DABOs/N-DABOs as HIV reverse transcriptase inhibitors

Radi, Marco, Pagano, Mafalda, Franchi, Luigi, Castagnolo, Daniele, Schenone, Silvia, Casaluce, Gianni, Zamperini, Claudio, Dreassi, Elena, Maga, Giovanni, Samuele, Alberta, Gonzalo, Encarna, Clotet, Bonaventura, Esté, José and Botta, Maurizio (2012) Synthesis, biological activity, and ADME properties of novel S-DABOs/N-DABOs as HIV reverse transcriptase inhibitors. ChemMedChem, 7 (5). pp. 883-896. ISSN 1860-7179

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Official URL: http://dx.doi.org/10.1002/cmdc.201200056

Abstract

Previous studies aimed at exploring the SAR of C2-functionalized S-DABOs demonstrated that the substituent at this position plays a key role in the inhibition of both wild-type RT and drug-resistant enzymes, particularly the K103N mutant form. The introduction of a cyclopropyl group led us to the discovery of a potent inhibitor with picomolar activity against wild-type RT and nanomolar activity against many key mutant forms such as K103N. Despite its excellent antiviral profile, this compound suffers from a suboptimal ADME profile typical of many S-DABO analogues, but it could, however, represent a promising candidate as an anti-HIV microbicide. In the present work, a new series of S-DABO/N-DABO derivatives were synthesized to obtain additional SAR information on the C2-position and in particular to improve ADME properties while maintaining a good activity profile against HIV-1 RT. In vitro ADME properties (PAMPA permeation, water solubility, and metabolic stability) were also experimentally evaluated for the most interesting compounds to obtain a reliable indication of their plasma levels after oral administration.

Item Type: Article
Uncontrolled Keywords: ADME, antiviral agents, lead optimization, NNRTIs, reverse transcriptase
Subjects: F100 Chemistry
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Linda Barlow
Date Deposited: 09 Jan 2013 09:22
Last Modified: 24 Oct 2017 11:25
URI: http://nrl.northumbria.ac.uk/id/eprint/10974

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