title: Heterobiaryl human immunodeficiency virus entry inhibitors.
abstract: Previously disclosed HIV (human immunodeficiency virus) attachment inhibitors, exemplified by BMS 806 (formally BMS378806, 1), are characterized by a substituted indole or azaindole ring linked to a benzoylpiperazine via a ketoamide or sulfonamide group. In the present report, we describe the discovery of a novel series of potent HIV entry inhibitors in which the indole or azaindole ring of previous inhibitors is replaced by a heterobiaryl group. Several of these analogues exhibited IC(50) values of less than 5 nM in a pseudotyped antiviral assay, and compound 13k was demonstrated to exhibit potency and selectivity similar to those of 1 against a panel of clinical viral isolates. Moreover, current structure-activity relationship studies of these novel biaryl gp120 inhibitors revealed that around the biaryl, a fine crevice might exist in the gp120 binding site. Taken in sum, these data reveal a hitherto unsuspected flexibility in the structure-activity relationships for these inhibitors and suggest new avenues for exploration and gp120 inhibitor design.
authors.affiliation: Trimeris, Inc, Morrisville, North Carolina 27560, USA. rongjian.lu@sequoiapharma.com
authors.forename: Rong-Jian
authors.initials: RJ
authors.lastname: Lu
authors.forename: John A
authors.initials: JA
authors.lastname: Tucker
authors.forename: Jason
authors.initials: J
authors.lastname: Pickens
authors.forename: You-An
authors.initials: YA
authors.lastname: Ma
authors.forename: Tatiana
authors.initials: T
authors.lastname: Zinevitch
authors.forename: Olga
authors.initials: O
authors.lastname: Kirichenko
authors.forename: Vitalii
authors.initials: V
authors.lastname: Konoplev
authors.forename: Svetlana
authors.initials: S
authors.lastname: Kuznetsova
authors.forename: Sergey
authors.initials: S
authors.lastname: Sviridov
authors.forename: Enugurthi
authors.initials: E
authors.lastname: Brahmachary
authors.forename: Alisher
authors.initials: A
authors.lastname: Khasanov
authors.forename: Charles
authors.initials: C
authors.lastname: Mikel
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Changhui
authors.initials: C
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Stephanie
authors.initials: S
authors.lastname: Freel
authors.forename: Shelly
authors.initials: S
authors.lastname: Fisher
authors.forename: Alana
authors.initials: A
authors.lastname: Sullivan
authors.forename: Jiying
authors.initials: J
authors.lastname: Zhou
authors.forename: Sherry
authors.initials: S
authors.lastname: Stanfield-Oakley
authors.forename: Brian
authors.initials: B
authors.lastname: Baker
authors.forename: Jeff
authors.initials: J
authors.lastname: Sailstad
authors.forename: Michael
authors.initials: M
authors.lastname: Greenberg
authors.forename: Dani
authors.initials: D
authors.lastname: Bolognesi
authors.forename: Brian
authors.initials: B
authors.lastname: Bray
authors.forename: Barney
authors.initials: B
authors.lastname: Koszalka
authors.forename: Peter
authors.initials: P
authors.lastname: Jeffs
authors.forename: Cynthia
authors.initials: C
authors.lastname: Jeffries
authors.forename: Alexander
authors.initials: A
authors.lastname: Chucholowski
authors.forename: Connie
authors.initials: C
authors.lastname: Sexton
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D006678:HIV / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; C451732:BMS 806; D007211:Indoles; D010879:Piperazines; C030374:indole