title: Design of orally bioavailable, symmetry-based inhibitors of HIV protease.
abstract: A series of novel inhibitors of HIV-1 protease with excellent oral bioavailability is described. Differential acylation of the two amino groups of symmetry-based diamine core groups 2-5 led to unsymmetrically substituted inhibitors 17-43, many of which inhibited HIV protease at subnanomolar concentrations. Anti-HIV activity in vitro was observed at 0.1-1 microM. A systematic evaluation of the pharmacokinetic behavior of these inhibitors in rats identified the influence of aqueous solubility, molecular size and hydrogen-bonding functionality. Compound 30 (A-80987) was selected for further evaluation based on a favorable Cmax/ ED50 ratio (> 20) and half-life (> 2 h).
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
authors.forename: L C
authors.initials: LC
authors.lastname: Fino
authors.forename: P
authors.initials: P
authors.lastname: Bryant
authors.forename: A
authors.initials: A
authors.lastname: Craig-Kennard
authors.forename: H L
authors.initials: HL
authors.lastname: Sham
authors.forename: C
authors.initials: C
authors.lastname: Zhao
authors.forename: S
authors.initials: S
authors.lastname: Vasavanonda
authors.forename: W E
authors.initials: WE
authors.lastname: Kohlbrenner
authors.forename: N E
authors.initials: NE
authors.lastname: Wideburg
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D001682:Biological Availability; D002478:Cells, Cultured; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008214:Lymphocytes / Q000821:virology; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors