title: Nonpeptidic HIV protease inhibitors: 4-hydroxy-pyran-2-one inhibitors with functional tethers to P1 phenyl ring to reach S3 pocket of the enzyme.
abstract: A systematic study of tethering various groups on 6-phenyl ring of 4-hydroxy-6-phenyl-3-[(2-isopropylphenyl)thio]pyran-2-one was performed to increase the binding affinity with HIV protease. This tethering approach was aimed to fill S3 pocket of the enzyme. Thus, tethering hydrophilic groups resulted in more potent inhibitors. Similarly, various aromatic hydrophobic rings as well as heterocyclic rings were explored as tethering substituents to alter the physical properties as well as to enhance the binding affinity with HIV protease. Inhibitor 24, 4-hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-(3-pyridinylmethoxy+ ++ ) phenyl]-2H-pyran-2-one, was evaluated as a prototypic lead structure to study various physical as well as pharmacological properties of this class of HIV protease inhibitors.
authors.affiliation: Department of Chemistry, Division of Warner-Lambert Company, Ann Arbor, Michigan 48106, USA.
authors.forename: J
authors.initials: J
authors.lastname: Vara Prasad
authors.forename: P J
authors.initials: PJ
authors.lastname: Tummino
authors.forename: D
authors.initials: D
authors.lastname: Ferguson
authors.forename: J
authors.initials: J
authors.lastname: Saunders
authors.forename: S
authors.initials: S
authors.lastname: Vander Roest
authors.forename: T J
authors.initials: TJ
authors.lastname: McQuade
authors.forename: A
authors.initials: A
authors.lastname: Heldsinger
authors.forename: E L
authors.initials: EL
authors.lastname: Reyner
authors.forename: B H
authors.initials: BH
authors.lastname: Stewart
authors.forename: R J
authors.initials: RJ
authors.lastname: Guttendorf
authors.forename: K S
authors.initials: KS
authors.lastname: Para
authors.forename: E A
authors.initials: EA
authors.lastname: Lunney
authors.forename: S J
authors.initials: SJ
authors.lastname: Gracheck
authors.forename: J M
authors.initials: JM
authors.lastname: Domagala
mesh_terms: D002460:Cell Line; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D015394:Molecular Structure; D011753:Pyrones / Q000737:chemistry*
chemical_list: C099351:4-hydroxy-6-phenyl-3-((2-isopropylphenyl)thio)pyran-2-one; D017320:HIV Protease Inhibitors; D011753:Pyrones