Triketoacid inhibitors of HIV-integrase: a new chemotype useful for probing the integrase pharmacophore.
Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. This study reports on the discovery of a new triketoacid-based chemotype that selectively inhibits the strand transfer reaction of HIV-integrase. SAR studies showed that the template binds to integrase in a manner similar to the diketoacid-based inhibitors. Moreover, comparison of the new chemotype to two different diketoacid templates led us to propose two aryl-binding domains in the inhibitor binding site. This information was used to design a new diketoacid template with improved activity against the enzyme.
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. walkerma@bms.com
Michael A
MA
Walker
Timothy
T
Johnson
Zhuping
Z
Ma
Jacques
J
Banville
Roger
R
Remillard
Oak
O
Kim
Yunhui
Y
Zhang
Andrew
A
Staab
Henry
H
Wong
Albert
A
Torri
Himadri
H
Samanta
Zeyu
Z
Lin
Carol
C
Deminie
Brian
B
Terry
Mark
M
Krystal
Nicholas
N
Meanwell
D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D007651:Keto Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D019427:HIV Integrase