title: Exploration of the diketoacid integrase inhibitor chemotype leading to the discovery of the anilide-ketoacids chemotype.
abstract: Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. A previous study of the diketoacid-based chemotype suggested that there are two aryl-binding domains on integrase. In this study, modifications to the indole-based diketoacid chemotype are explored. It is demonstrated that the indole group can be replaced with secondary but not tertiary (e.g., N-methyl) aniline-based amides without sacrificing in vitro inhibitory activity. The difference in activity between the secondary and tertiary amides is most likely due to the opposite conformational preferences of the amide bonds, s-trans for the secondary-amide and s-cis for the tertiary-amide. However, it was found that the conformational preference of the tertiary amide can be reversed by incorporating the amide nitrogen atom into an indoline heterocycle, resulting in very potent integrase inhibitors.
authors.affiliation: Department of Medicinal Chemistry, Pharmaceutical Research Institute, Bristol-Myers Squibb, The Richard L Gelb Center for Pharmaceutical Research and Development, 5 Research Parkway Wallingford, CT 06492, USA. michael.a.walker@bms.com
authors.forename: Michael A
authors.initials: MA
authors.lastname: Walker
authors.forename: Timothy
authors.initials: T
authors.lastname: Johnson
authors.forename: Zhuping
authors.initials: Z
authors.lastname: Ma
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jacques
authors.initials: J
authors.lastname: Banville
authors.forename: Roger
authors.initials: R
authors.lastname: Remillard
authors.forename: Serge
authors.initials: S
authors.lastname: Plamondon
authors.forename: Annapurna
authors.initials: A
authors.lastname: Pendri
authors.forename: Henry
authors.initials: H
authors.lastname: Wong
authors.forename: Daniel
authors.initials: D
authors.lastname: Smith
authors.forename: Albert
authors.initials: A
authors.lastname: Torri
authors.forename: Himadri
authors.initials: H
authors.lastname: Samanta
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Lin
authors.forename: Carol
authors.initials: C
authors.lastname: Deminie
authors.forename: Brian
authors.initials: B
authors.lastname: Terry
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
authors.forename: Nicholas
authors.initials: N
authors.lastname: Meanwell
mesh_terms: D000577:Amides / Q000737:chemistry; D000813:Anilides / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D002412:Cations; D015195:Drug Design; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007651:Keto Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D008274:Magnesium / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000813:Anilides; D002412:Cations; D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D008274:Magnesium