title: Inhibitors of HIV-1 maturation: Development of structure-activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids.
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.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: jacob.swidorski@bms.com.
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Swidorski
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Sing-Yuen
authors.initials: SY
authors.lastname: Sit
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Ny
authors.initials: N
authors.lastname: Sin
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Venables
authors.affiliation: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Dawn D
authors.initials: DD
authors.lastname: Parker
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Beata
authors.initials: B
authors.lastname: Nowicka-Sans
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Terry
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Tricia
authors.initials: T
authors.lastname: Protack
authors.affiliation: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Rahematpura
authors.affiliation: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Umesh
authors.initials: U
authors.lastname: Hanumegowda
authors.affiliation: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Jenkins
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Ira B
authors.initials: IB
authors.lastname: Dicker
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Regueiro-Ren
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D001565:Benzoates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006678:HIV / Q000187:drug effects* / Q000254:growth & development*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000577:Amides; D019380:Anti-HIV Agents; D001565:Benzoates; D014315:Triterpenes
keywords: Benzoic acid; Betulinic acid; C-28 amide; HIV-1; Maturation inhibitor; Triterpenoid