title: New, potent P1/P2-morpholinone-based HIV-protease inhibitors.
abstract: We have developed efficient synthesis of morpholinone-based cyclic mimetics of the P1/P2 portion of the HIV-1 protease inhibitor Amprenavir. This effort led to discovery of allyl- and spiro-cyclopropyl-P2-substituted inhibitors 17 and 31, both 500 times more potent than the parent inhibitor 1. These results support morpholinones as novel mimetics of the P1/P2 portion of Amprenavir and potentially of other HIV-protease inhibitors, and thus provide a novel medicinal chemistry template for optimization toward more potent and drug-like inhibitors.
authors.affiliation: GlaxoSmithKline, MV CEDD, Five Moore Drive, Research Triangle Park, NC 27709, USA. wieslaw.m.kazmierski@gsk.com
authors.forename: Wieslaw M
authors.initials: WM
authors.lastname: Kazmierski
authors.forename: Eric
authors.initials: E
authors.lastname: Furfine
authors.forename: Andrew
authors.initials: A
authors.lastname: Spaltenstein
authors.forename: Lois L
authors.initials: LL
authors.lastname: Wright
mesh_terms: D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D018716:Molecular Mimicry; D009025:Morpholines / Q000138:chemical synthesis* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides
chemical_list: D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D009025:Morpholines; D010456:Peptides, Cyclic; D013449:Sulfonamides; C095108:amprenavir