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.
Synthesis, Biological Activity, and ADME Properties of Novel S-DABOs/N-DABOs as HIV Reverse Transcriptase Inhibitors / Marco Radi; Mafalda Pagano; Luigi Franchi; Daniele Castagnolo; Silvia Schenone; Gianni Casaluce; Claudio Zamperini; Elena Dreassi; Giovanni Maga; Alberta Samuele; Encarna Gonzalo; Bonaventura Clotet;Josè A. Esté; Maurizio Botta. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 7(2012), pp. 883-896. [10.1002/cmdc.201200056]