title: Inhibitors of HIV-1 attachment: The discovery and structure-activity relationships of tetrahydroisoquinolines as replacements for the piperazine benzamide in the 3-glyoxylyl 6-azaindole pharmacophore.
abstract: 6,6-Fused ring systems including tetrahydroisoquinolines and tetrahydropyrido[3,4-d]pyrimidines have been explored as possible replacements for the piperazine benzamide portion of the HIV-1 attachment inhibitor BMS-663068. In initial studies, the tetrahydroisoquinoline compounds demonstrate sub-nanomolar activity in a HIV-1 pseudotype viral infection assay used as the initial screen for inhibitory activity. Analysis of SARs and approaches to optimization for an improved drug-like profile are examined herein.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
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: Zhiwei
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Carini
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: Ming
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Johnson
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Pin-Fang
authors.initials: PF
authors.lastname: Lin
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 Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Wenying
authors.initials: W
authors.lastname: Li
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: Lawrence G
authors.initials: LG
authors.lastname: Hamann
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: D001372:Aza Compounds / Q000737:chemistry*; D001549:Benzamides / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors / Q000235:genetics; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053585:Virus Attachment / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: C504762:6-azaindole; D001372:Aza Compounds; D001549:Benzamides; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D007211:Indoles; D010879:Piperazines; D044005:Tetrahydroisoquinolines
keywords: Attachment; BMS-663068; Entry; HIV-1; Tetrahydroisoquinoline; Tetrahydropyrido[3,4-d]pyrimidines