title: Design of HIV-1 protease inhibitors active on multidrug-resistant virus.
abstract: On the basis of structural data gathered during our ongoing HIV-1 protease inhibitors program, from which our clinical candidate TMC114 9 was selected, we have discovered new series of fused heteroaromatic sulfonamides. The further extension into the P2' region was aimed at identifying new classes of compounds with an improved broad spectrum activity and acceptable pharmacokinetic properties. Several of these compounds display an exceptional broad spectrum activity against a panel of highly cross-resistant mutants. Certain members of these series exhibit favorable pharmacokinetic profiles in rat and dog. Crystal structures and molecular modeling were used to rationalize the broad spectrum profile resulting from the extension into the P2' pocket of the HIV-1 protease.
authors.affiliation: Tibotec BVBA, Generaal de Wittelaan L 11B 3, B-2800 Mechelen, Belgium.
authors.forename: Dominique L N G
authors.initials: DL
authors.lastname: Surleraux
authors.forename: Herman A
authors.initials: HA
authors.lastname: de Kock
authors.forename: Wim G
authors.initials: WG
authors.lastname: Verschueren
authors.forename: Geert M E
authors.initials: GM
authors.lastname: Pille
authors.forename: Louis J R
authors.initials: LJ
authors.lastname: Maes
authors.forename: Anik
authors.initials: A
authors.lastname: Peeters
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vendeville
authors.forename: Sandra
authors.initials: S
authors.lastname: De Meyer
authors.forename: Hilde
authors.initials: H
authors.lastname: Azijn
authors.forename: Rudi
authors.initials: R
authors.lastname: Pauwels
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: de Bethune
authors.forename: Nancy M
authors.initials: NM
authors.lastname: King
authors.forename: Moses
authors.initials: M
authors.lastname: Prabu-Jeyabalan
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
authors.forename: Piet B T P
authors.initials: PB
authors.lastname: Wigerinck
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002151:Calorimetry; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D024921:Drug Resistance, Multiple, Viral; D004355:Drug Stability; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001583:Benzoxazoles; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D013844:Thiazoles