In:
ChemMedChem, Wiley, Vol. 7, No. 5 ( 2012-05), p. 883-896
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.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201200056
Language:
English
Publisher:
Wiley
Publication Date:
2012
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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