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
Rong-Jian
RJ
Trimeris, Inc, Morrisville, North Carolina 27560, USA. rongjian.lu@sequoiapharma.com
Tucker
John A
JA
Pickens
Jason
J
Ma
You-An
YA
Zinevitch
Tatiana
T
Kirichenko
Olga
O
Konoplev
Vitalii
V
Kuznetsova
Svetlana
S
Sviridov
Sergey
S
Brahmachary
Enugurthi
E
Khasanov
Alisher
A
Mikel
Charles
C
Yang
Yang
Y
Liu
Changhui
C
Wang
Jian
J
Freel
Stephanie
S
Fisher
Shelly
S
Sullivan
Alana
A
Zhou
Jiying
J
Stanfield-Oakley
Sherry
S
Baker
Brian
B
Sailstad
Jeff
J
Greenberg
Michael
M
Bolognesi
Dani
D
Bray
Brian
B
Koszalka
Barney
B
Jeffs
Peter
P
Jeffries
Cynthia
C
Chucholowski
Alexander
A
Sexton
Connie
C
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
D019380:Anti-HIV Agents; C451732:BMS 806; D007211:Indoles; D010879:Piperazines; C030374:indole