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 / Radi, Marco; 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]

Synthesis, Biological Activity, and ADME Properties of Novel S-DABOs/N-DABOs as HIV Reverse Transcriptase Inhibitors

RADI, Marco;
2012-01-01

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.
2012
Synthesis, Biological Activity, and ADME Properties of Novel S-DABOs/N-DABOs as HIV Reverse Transcriptase Inhibitors / Radi, Marco; 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]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2432128
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