title: Symmetry-based inhibitors of HIV protease. Structure-activity studies of acylated 2,4-diamino-1,5-diphenyl-3-hydroxypentane and 2,5-diamino-1,6-diphenylhexane-3,4-diol.
abstract: The structure-activity relationships in two series of novel, symmetry-based inhibitors of HIV protease, the enzyme responsible for maturation of the human immunodeficiency virus, are described. Beginning with lead compounds 3-6, the effect of adding polar, heterocyclic end groups to one or both ends of the symmetric or pseudosymmetric inhibitors was probed. Aqueous solubility was enhanced > 1000-fold while maintaining potent inhibition of purified HIV-1 protease and anti-HIV activity in vitro. Pharmacokinetic studies in rats indicated a substantial difference in the absorption properties of mono-ol-based and diol-based inhibitors. The oral bioavailability of inhibitor 19 in rats was 19%; however, the Cmax obtained failed to exceed the anti-HIV EC50 in vitro. Substantial plasma levels of potent inhibitors of the diol class were not obtained after oral administration in rats; however, the optimal combination of aqueous solubility and in vitro antiviral activity of several inhibitors support their potential use in intravenous therapy.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: L
authors.initials: L
authors.lastname: Codacovi
authors.forename: X C
authors.initials: XC
authors.lastname: Wang
authors.forename: W E
authors.initials: WE
authors.lastname: Kohlbrenner
authors.forename: N E
authors.initials: NE
authors.lastname: Wideburg
authors.forename: A
authors.initials: A
authors.lastname: Saldivar
authors.forename: S
authors.initials: S
authors.lastname: Vasavanonda
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
authors.forename: P
authors.initials: P
authors.lastname: Bryant
authors.forename: H L
authors.initials: HL
authors.lastname: Sham
mesh_terms: D000605:Amino Alcohols / Q000737:chemistry* / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D003959:Diamines / Q000737:chemistry* / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000605:Amino Alcohols; D003959:Diamines; D017320:HIV Protease Inhibitors