Heterobiaryl human immunodeficiency virus entry inhibitors.
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.
Lu, R-J; Tucker, JA; Pickens, J; Ma, Y-A; Zinevitch, T; Kirichenko, O; Konoplev, V; Kuznetsova, S; Sviridov, S; Brahmachary, E; Khasanov, A; Mikel, C; Yang, Y; Liu, C; Wang, J; Freel, S; Fisher, S; Sullivan, A; Zhou, J; Stanfield-Oakley, S; Baker, B; Sailstad, J; Greenberg, M; Bolognesi, D; Bray, B; Koszalka, B; Jeffs, P; Jeffries, C; Chucholowski, A; Sexton, C
Volume / Issue
Start / End Page
Pubmed Central ID
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)