Exploration of the diketoacid integrase inhibitor chemotype leading to the discovery of the anilide-ketoacids chemotype.
Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. A previous study of the diketoacid-based chemotype suggested that there are two aryl-binding domains on integrase. In this study, modifications to the indole-based diketoacid chemotype are explored. It is demonstrated that the indole group can be replaced with secondary but not tertiary (e.g., N-methyl) aniline-based amides without sacrificing in vitro inhibitory activity. The difference in activity between the secondary and tertiary amides is most likely due to the opposite conformational preferences of the amide bonds, s-trans for the secondary-amide and s-cis for the tertiary-amide. However, it was found that the conformational preference of the tertiary amide can be reversed by incorporating the amide nitrogen atom into an indoline heterocycle, resulting in very potent integrase inhibitors.
Walker
Michael A
MA
Department of Medicinal Chemistry, Pharmaceutical Research Institute, Bristol-Myers Squibb, The Richard L Gelb Center for Pharmaceutical Research and Development, 5 Research Parkway Wallingford, CT 06492, USA. michael.a.walker@bms.com
Johnson
Timothy
T
Ma
Zhuping
Z
Zhang
Yunhui
Y
Banville
Jacques
J
Remillard
Roger
R
Plamondon
Serge
S
Pendri
Annapurna
A
Wong
Henry
H
Smith
Daniel
D
Torri
Albert
A
Samanta
Himadri
H
Lin
Zeyu
Z
Deminie
Carol
C
Terry
Brian
B
Krystal
Mark
M
Meanwell
Nicholas
N
D000577:Amides / Q000737:chemistry; D000813:Anilides / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D002412:Cations; D015195:Drug Design; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007651:Keto Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D008274:Magnesium / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D000813:Anilides; D002412:Cations; D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D008274:Magnesium