Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment. 12. Structure-activity relationships associated with 4-fluoro-6-azaindole derivatives leading to the identification of 1-(4-benzoylpiperazin-1-yl)-2-(4-fluoro-7-[1,2,3]triazol-1-yl-1h-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-585248).
A series of highly potent HIV-1 attachment inhibitors with 4-fluoro-6-azaindole core heterocycles that target the viral envelope protein gp120 has been prepared. Substitution in the 7-position of the azaindole core with amides (12a,b), C-linked heterocycles (12c-l), and N-linked heterocycles (12m-u) provided compounds with subnanomolar potency in a pseudotype infectivity assay and good pharmacokinetic profiles in vivo. A predictive model was developed from the initial SAR in which the potency of the analogues correlated with the ability of the substituent in the 7-position of the azaindole to adopt a coplanar conformation by either forming internal hydrogen bonds or avoiding repulsive substitution patterns. 1-(4-Benzoylpiperazin-1-yl)-2-(4-fluoro-7-[1,2,3]triazol-1-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-585248, 12m) exhibited much improved in vitro potency and pharmacokinetic properties than the previous clinical candidate BMS-488043 (1). The predicted low clearance in humans, modest protein binding, and good potency in the presence of 40% human serum for 12m led to its selection for human clinical studies.
Department of Medicinal Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States. alicia.regueiroren@bms.com
Alicia
A
Regueiro-Ren
Qiufen M
QM
Xue
Jacob J
JJ
Swidorski
Yi-Fei
YF
Gong
Marina
M
Mathew
Dawn D
DD
Parker
Zheng
Z
Yang
Betsy
B
Eggers
Celia
C
D'Arienzo
Yongnian
Y
Sun
Jacek
J
Malinowski
Qi
Q
Gao
Dedong
D
Wu
David R
DR
Langley
Richard J
RJ
Colonno
Caly
C
Chien
Dennis M
DM
Grasela
Ming
M
Zheng
Pin-Fang
PF
Lin
Nicholas A
NA
Meanwell
John F
JF
Kadow
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011789:Quantum Theory; D051381:Rats; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D053585:Virus Attachment / Q000187:drug effects
C582545:1-(4-benzoyl-piperazin-1-yl)-2-(4-fluoro-7-(1,2,3)triazol-1-yl-1H-pyrrolo(2,3-c)pyridin-3-yl)-ethane-1,2-dione; D019380:Anti-HIV Agents; D007211:Indoles; D010879:Piperazines; D011725:Pyridines; D011758:Pyrroles; D014227:Triazines; D014230:Triazoles