title: Structure-based design of nonpeptidic HIV protease inhibitors: the sulfonamide-substituted cyclooctylpyramones.
abstract: Recently, cyclooctylpyranone derivatives with m-carboxamide substituents (e.g. 2c) were identified as potent, nonpeptidic HIV protease inhibitors, but these compounds lacked significant antiviral activity in cell culture. Substitution of a sulfonamide group at the meta position, however, produces compounds with excellent HIV protease binding affinity and antiviral activity. Guided by an iterative structure-based drug design process, we have prepared and evaluated a number of these derivatives, which are readily available via a seven-step synthesis. A few of the most potent compounds were further evaluated for such characteristics as pharmacokinetics and toxicity in rats and dogs. From this work, the p-cyanophenyl sulfonamide derivative 35k emerged as a promising inhibitor, was selected for further development, and entered phase I clinical trials.
authors.affiliation: Discovery Chemistry Research, Pharmacia and Upjohn, Kalamazoo, Michigan 49001, USA.
authors.forename: H I
authors.initials: HI
authors.lastname: Skulnick
authors.forename: P D
authors.initials: PD
authors.lastname: Johnson
authors.forename: P A
authors.initials: PA
authors.lastname: Aristoff
authors.forename: J K
authors.initials: JK
authors.lastname: Morris
authors.forename: K D
authors.initials: KD
authors.lastname: Lovasz
authors.forename: W J
authors.initials: WJ
authors.lastname: Howe
authors.forename: K D
authors.initials: KD
authors.lastname: Watenpaugh
authors.forename: M N
authors.initials: MN
authors.lastname: Janakiraman
authors.forename: D J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: R J
authors.initials: RJ
authors.lastname: Reischer
authors.forename: T M
authors.initials: TM
authors.lastname: Schwartz
authors.forename: L S
authors.initials: LS
authors.lastname: Banitt
authors.forename: P K
authors.initials: PK
authors.lastname: Tomich
authors.forename: J C
authors.initials: JC
authors.lastname: Lynn
authors.forename: M M
authors.initials: MM
authors.lastname: Horng
authors.forename: K T
authors.initials: KT
authors.lastname: Chong
authors.forename: R R
authors.initials: RR
authors.lastname: Hinshaw
authors.forename: L A
authors.initials: LA
authors.lastname: Dolak
authors.forename: E P
authors.initials: EP
authors.lastname: Seest
authors.forename: F J
authors.initials: FJ
authors.lastname: Schwende
authors.forename: B D
authors.initials: BD
authors.lastname: Rush
authors.forename: G M
authors.initials: GM
authors.lastname: Howard
authors.forename: L N
authors.initials: LN
authors.lastname: Toth
authors.forename: K R
authors.initials: KR
authors.lastname: Wilkinson
authors.forename: K R
authors.initials: KR
authors.lastname: Romines
mesh_terms: D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008958:Models, Molecular; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D017320:HIV Protease Inhibitors; D011753:Pyrones; D013449:Sulfonamides