title: A novel, picomolar inhibitor of human immunodeficiency virus type 1 protease.
abstract: The design, synthesis, and molecular modeling studies of a novel series of azacyclic ureas, which are inhibitors of human immunodeficiency virus type 1 (HIV-1) protease that incorporate different ligands for the S1', S2, and S2' substrate-binding sites of HIV-1 protease are described. The synthesis of this series is highly flexible in the sense that the P1', P2, and P2' residues of the inhibitors can be changed independently. Molecular modeling studies on the phenyl ring of the P2 and P2' ligand suggested incorporation of hydrogen-bonding donor/acceptor groups at the 3' and 4-positions of the phenyl ring should increase binding potency. This led to the discovery of compound 7f (A-98881), which possesses high potency in the HIV-1 protease inhibition assay and the in vitro MT-4 cell culture assay (Ki = approximately 5 pM and EC50 = 0.002 microM). This compares well with the symmetrical cyclic urea 1 pioneered at DuPont Merck.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500.
authors.forename: H L
authors.initials: HL
authors.lastname: Sham
authors.forename: C
authors.initials: C
authors.lastname: Zhao
authors.forename: K D
authors.initials: KD
authors.lastname: Stewart
authors.forename: D A
authors.initials: DA
authors.lastname: Betebenner
authors.forename: S
authors.initials: S
authors.lastname: Lin
authors.forename: C H
authors.initials: CH
authors.lastname: Park
authors.forename: X P
authors.initials: XP
authors.lastname: Kong
authors.forename: W
authors.initials: W
authors.lastname: Rosenbrook
authors.forename: T
authors.initials: T
authors.lastname: Herrin
authors.forename: D
authors.initials: D
authors.lastname: Madigan
authors.forename: S
authors.initials: S
authors.lastname: Vasavanonda
authors.forename: N
authors.initials: N
authors.lastname: Lyons
authors.forename: A
authors.initials: A
authors.lastname: Molla
authors.forename: A
authors.initials: A
authors.lastname: Saldivar
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
authors.forename: E
authors.initials: E
authors.lastname: McDonald
authors.forename: N E
authors.initials: NE
authors.lastname: Wideburg
authors.forename: J F
authors.initials: JF
authors.lastname: Denissen
authors.forename: T
authors.initials: T
authors.lastname: Robins
authors.forename: D J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: J J
authors.initials: JJ
authors.lastname: Plattner
authors.forename: D W
authors.initials: DW
authors.lastname: Norbeck
mesh_terms: D001665:Binding Sites; D004352:Drug Resistance, Microbial; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D008958:Models, Molecular
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease