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Synthesis, Biological Activity, and ADME Properties of Novel S ‐DABOs/ N ‐DABOs as HIV Reverse Transcriptase Inhibitors
Author(s) -
Radi Marco,
Pagano Mafalda,
Franchi Luigi,
Castagnolo Daniele,
Sche Silvia,
Casaluce Gianni,
Zamperini Claudio,
Dreassi Elena,
Maga Giovanni,
Samuele Alberta,
Gonzalo Encarna,
Clotet Bonaventura,
Esté José A.,
Botta Maurizio
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200056
Subject(s) - adme , reverse transcriptase , chemistry , drug discovery , human immunodeficiency virus (hiv) , mutant , pharmacology , enzyme , stereochemistry , in vitro , biochemistry , biology , virology , rna , gene
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.