title: Nonpeptidic potent HIV-1 protease inhibitors.
abstract: From an initial mass screening lead, (IC50: 3 microM) and information derived from the X-ray crystallographic structure of a related analog, complexed with HIV protease (PR), the design of more potent inhibitors has been advanced. Various structure-guided approaches to fill P1' and P2' pockets using this pyran-2-one template, molecular modeling and X-ray crystallographic studies led to potent compounds. Of particular significance to the design of this series of inhibitors is the displacement of key structural waters. The binding modes of a series of pyran-2-one analogs and comparison of binding modes with different pyran-2-ones, are highlighted. Noteworthy was the discovery of a highly potent (IC50: 0.007 microM) pyran-2-one derivative, containing novel P1' and P2' functionalization and possessing no chiral centers and having low molecular weight. Pyran-2-ones possessing appended groups to reach to the S3 pocket of the enzyme via tethering on the 6-phenyl ring of pyran-2-one ring is also discussed.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48106-1047, USA.
authors.forename: J V
authors.initials: JV
authors.lastname: Prasad
authors.forename: E A
authors.initials: EA
authors.lastname: Lunney
authors.forename: K S
authors.initials: KS
authors.lastname: Para
authors.forename: P J
authors.initials: PJ
authors.lastname: Tummino
authors.forename: D
authors.initials: D
authors.lastname: Ferguson
authors.forename: D
authors.initials: D
authors.lastname: Hupe
authors.forename: J M
authors.initials: JM
authors.lastname: Domagala
authors.forename: J W
authors.initials: JW
authors.lastname: Erickson
mesh_terms: D018938:Caco-2 Cells / Q000378:metabolism; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D011714:Pyrans