期刊
CHEMMEDCHEM
卷 7, 期 5, 页码 883-896出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201200056
关键词
ADME; antiviral agents; lead optimization; NNRTIs; reverse transcriptase
资金
- European Union (CHAARM) [HEALTHF3-2009-242135]
- European Union (THINC) [HEALTH-2007-2.3.2-1]
- National AIDS Program [40H26]
- MICINN [SAF2010-216117-C02]
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.
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