title: Microwave-accelerated synthesis of P1'-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Jenny K
authors.initials: JK
authors.lastname: Ekegren
authors.forename: Nina
authors.initials: N
authors.lastname: Ginman
authors.forename: Asa
authors.initials: A
authors.lastname: Johansson
authors.forename: Hans
authors.initials: H
authors.lastname: Wallberg
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Torsten
authors.initials: T
authors.lastname: Unge
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
mesh_terms: 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
chemical_list: D000438:Alcohols; D017320:HIV Protease Inhibitors; D007189:Indans; D010165:Palladium; D016333:HIV Protease