title: Synthesis, antiviral activity, and bioavailability studies of gamma-lactam derived HIV protease inhibitors.
abstract: Incorporation of a gamma-lactam in hydroxyethylene isosteres results in modest inhibitors of HIV-1 protease. Additional structural activity studies have produced significantly more potent inhibitors with the introduction of the trisubstituted cyclopentane (see compound 20) as the optimum substituent for the C-terminus. This new amino acid amide surrogate can be readily prepared in large scale from (R)-pulegone. Optimized compounds (36) and (60) are potent antiviral agents and are well absorbed (15-20%) in a dog model after oral administration.
authors.affiliation: Merck Research Laboratories, West Point, PA 19486.
authors.forename: R W
authors.initials: RW
authors.lastname: Hungate
authors.forename: J L
authors.initials: JL
authors.lastname: Chen
authors.forename: K E
authors.initials: KE
authors.lastname: Starbuck
authors.forename: J P
authors.initials: JP
authors.lastname: Vacca
authors.forename: S L
authors.initials: SL
authors.lastname: McDaniel
authors.forename: R B
authors.initials: RB
authors.lastname: Levin
authors.forename: B D
authors.initials: BD
authors.lastname: Dorsey
authors.forename: J P
authors.initials: JP
authors.lastname: Guare
authors.forename: M K
authors.initials: MK
authors.lastname: Holloway
authors.forename: W
authors.initials: W
authors.lastname: Whitter
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004285:Dogs; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D007769:Lactams