Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment. 5. An evolution from indole to azaindoles leading to the discovery of 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043), a drug candidate that demonstrates antiviral activity in HIV-1-infected subjects.
Azaindole derivatives derived from the screening lead 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1) were prepared and characterized to assess their potential as inhibitors of HIV-1 attachment. Systematic replacement of each of the unfused carbon atoms in the phenyl ring of the indole moiety by a nitrogen atom provided four different azaindole derivatives that displayed a clear SAR for antiviral activity and all of which displayed marked improvements in pharmaceutical properties. Optimization of these azaindole leads resulted in the identification of two compounds that were advanced to clinical studies: (R)-1-(4-benzoyl-2-methylpiperazin-1-yl)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione (BMS-377806, 3) and 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043, 4). In a preliminary clinical study, 4 administered as monotherapy for 8 days, reduced viremia in HIV-1-infected subjects, providing proof of concept for this mechanistic class.
Wang
Tao
T
Departments of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. tao.wang@bms.com
Yin
Zhiwei
Z
Zhang
Zhongxing
Z
Bender
John A
JA
Yang
Zhong
Z
Johnson
Graham
G
Yang
Zheng
Z
Zadjura
Lisa M
LM
D'Arienzo
Celia J
CJ
DiGiugno Parker
Dawn
D
Gesenberg
Christophe
C
Yamanaka
Gregory A
GA
Gong
Yi-Fei
YF
Ho
Hsu-Tso
HT
Fang
Hua
H
Zhou
Nannan
N
McAuliffe
Brian V
BV
Eggers
Betsy J
BJ
Fan
Li
L
Nowicka-Sans
Beata
B
Dicker
Ira B
IB
Gao
Qi
Q
Colonno
Richard J
RJ
Lin
Pin-Fang
PF
Meanwell
Nicholas A
NA
Kadow
John F
JF
D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D055808:Drug Discovery; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D019289:Pyruvic Acid; D051381:Rats; D015203:Reproducibility of Results; D053585:Virus Attachment / Q000187:drug effects*
D019380:Anti-HIV Agents; C477855:BMS-378806; D007211:Indoles; D010879:Piperazines; D019289:Pyruvic Acid; C509651:BMS-488043