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Inhibitors of HIV-1 maturation: Development of structure-activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2016 Apr 15; Vol. 26 (8), pp. 1925-30. Date of Electronic Publication: 2016 Mar 08. - Publication Year :
- 2016
-
Abstract
- We have recently reported on the discovery of a C-3 benzoic acid (1) as a suitable replacement for the dimethyl succinate side chain of bevirimat (2), an HIV-1 maturation inhibitor that reached Phase II clinical trials before being discontinued. Recent SAR studies aimed at improving the antiviral properties of 2 have shown that the benzoic acid moiety conferred topographical constraint to the pharmacophore and was associated with a lower shift in potency in the presence of human serum albumin. In this manuscript, we describe efforts to improve the polymorphic coverage of the C-3 benzoic acid chemotype through modifications at the C-28 position of the triterpenoid core. The dimethylaminoethyl amides 17 and 23 delivered improved potency toward bevirimat-resistant viruses while increasing C24 in rat oral PK studies.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Subjects :
- Administration, Oral
Amides administration & dosage
Amides chemistry
Animals
Anti-HIV Agents administration & dosage
Benzoates administration & dosage
Benzoates chemistry
Dose-Response Relationship, Drug
Humans
Microbial Sensitivity Tests
Microsomes, Liver drug effects
Microsomes, Liver metabolism
Molecular Structure
Rats
Structure-Activity Relationship
Triterpenes administration & dosage
Triterpenes chemistry
Amides pharmacology
Anti-HIV Agents chemistry
Anti-HIV Agents pharmacology
Benzoates pharmacology
HIV drug effects
HIV growth & development
Triterpenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 26
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 26988305
- Full Text :
- https://doi.org/10.1016/j.bmcl.2016.03.019