Microwave-accelerated synthesis of P1'-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold.
Two series of P1'-extended HIV-1 protease inhibitors comprising a tertiary alcohol in the transition-state mimic exhibiting Ki values ranging from 2.1 to 93 nM have been synthesized. Microwave-accelerated palladium-catalyzed cross-couplings were utilized to rapidly optimize the P1' side chain. High cellular antiviral potencies were encountered when the P1' benzyl group was elongated with a 3- or 4-pyridyl substituent (EC50 = 0.18-0.22 microM). X-ray crystallographic data were obtained for three inhibitors cocrystallized with the enzyme.
Ekegren
Jenny K
JK
Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
Ginman
Nina
N
Johansson
Asa
A
Wallberg
Hans
H
Larhed
Mats
M
Samuelsson
Bertil
B
Unge
Torsten
T
Hallberg
Anders
A
D000438:Alcohols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002384:Catalysis; D002460:Cell Line; D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D006860:Hydrogen Bonding; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008872:Microwaves; D018716:Molecular Mimicry; D010165:Palladium
D000438:Alcohols; D017320:HIV Protease Inhibitors; D007189:Indans; D010165:Palladium; D016333:HIV Protease