title: Potent HIV protease inhibitors containing a novel (hydroxyethyl)amide isostere.
abstract: A series of HIV protease inhibitors containing a novel (hydroxyethyl)amidosuccinoyl core has been synthesized. These peptidomimetic structures inhibit viral protease activity at low nanomolar concentrations (IC50 < 10 nM for HIV-1 protease). The inhibition constant (Ki) for inhibitor 19 was determined to be 7.5 pM against HIV-1 and 1.2 nM against HIV-2 proteases, respectively. Several compounds (19-24) inhibited HIV-1 replication in cell culture assays with 50% effective concentrations (EC50) = 3.7-35 nM. This series of inhibitors was found to exhibit poor bioavailability (< 10%) in the rat, following oral administration. The synthesis and biological properties of these compounds are discussed. In addition, an X-ray structure of one of these inhibitors (23) in complex with HIV-2 protease provides insight into the binding mode of this novel class of HIV protease inhibitors.
authors.affiliation: Bio-Méga Research Division, Boehringer Ingelheim (Canada) Ltd., Laval (Québec), Canada.
authors.forename: P L
authors.initials: PL
authors.lastname: Beaulieu
authors.forename: D
authors.initials: D
authors.lastname: Wernic
authors.forename: A
authors.initials: A
authors.lastname: Abraham
authors.forename: P C
authors.initials: PC
authors.lastname: Anderson
authors.forename: T
authors.initials: T
authors.lastname: Bogri
authors.forename: Y
authors.initials: Y
authors.lastname: Bousquet
authors.forename: G
authors.initials: G
authors.lastname: Croteau
authors.forename: I
authors.initials: I
authors.lastname: Guse
authors.forename: D
authors.initials: D
authors.lastname: Lamarre
authors.forename: F
authors.initials: F
authors.lastname: Liard
authors.forename: W
authors.initials: W
authors.lastname: Paris
authors.forename: D
authors.initials: D
authors.lastname: Thibeault
authors.forename: S
authors.initials: S
authors.lastname: Pav
authors.forename: L
authors.initials: L
authors.lastname: Tong
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D001682:Biological Availability; D002219:Carbamates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D015498:HIV-2 / Q000201:enzymology; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011487:Protein Conformation; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014633:Valine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D002219:Carbamates; D016655:HIV Core Protein p24; D017320:HIV Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; D016333:HIV Protease; C065184:p16 protease, Human immunodeficiency virus 2; D014633:Valine