Heterobiaryl human immunodeficiency virus entry inhibitors

  • J Med Chem. 2009 Jul 23;52(14):4481-7. doi: 10.1021/jm900330x.
Rong-Jian Lu  1 ,  John A Tucker ,  Jason Pickens ,  You-An Ma ,  Tatiana Zinevitch ,  Olga Kirichenko ,  Vitalii Konoplev ,  Svetlana Kuznetsova ,  Sergey Sviridov ,  Enugurthi Brahmachary ,  Alisher Khasanov ,  Charles Mikel ,  Yang Yang ,  Changhui Liu ,  Jian Wang ,  Stephanie Freel ,  Shelly Fisher ,  Alana Sullivan ,  Jiying Zhou ,  Sherry Stanfield-Oakley ,  Brian Baker ,  Jeff Sailstad ,  Michael Greenberg ,  Dani Bolognesi ,  Brian Bray ,  Barney Koszalka ,  Peter Jeffs ,  Cynthia Jeffries ,  Alexander Chucholowski ,  Connie Sexton
Affiliations
PMID: 19534463 DOI: 10.1021/jm900330x
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.