title: Benzoxazole and benzothiazole amides as novel pharmacokinetic enhancers of HIV protease inhibitors.
abstract: A new class of benzoxazole and benzothiazole amide derivatives exhibiting potent CYP3A4 inhibiting properties was identified. Extensive lead optimization was aimed at improving the CYP3A4 inhibitory properties as well as overall ADME profile of these amide derivatives. This led to the identification of thiazol-5-ylmethyl (2S,3R)-4-(2-(ethyl(methyl)amino)-N-isobutylbenzo[d]oxazole-6-carboxamido)-3-hydroxy-1-phenylbutan-2-ylcarbamate (C1) as a lead candidate for this class. This compound together with structurally similar analogues demonstrated excellent 'boosting' properties when tested in dogs. These findings warrant further evaluation of their properties in an effort to identify valuable alternatives to Ritonavir as pharmacokinetic enhancers.
authors: Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium. tjoncker@its.jnj.com
authors: Tim H M
authors: TH
authors: Jonckers
authors: Marie-Claude
authors: MC
authors: Rouan
authors: Geerwin
authors: G
authors: Haché
authors: Wim
authors: W
authors: Schepens
authors: Sabine
authors: S
authors: Hallenberger
authors: Judith
authors: J
authors: Baumeister
authors: Jennifer C
authors: JC
authors: Sasaki
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry*; D001583:Benzoxazoles / Q000737:chemistry*; D018938:Caco-2 Cells; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004285:Dogs; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D015497:HIV-1 / Q000201:enzymology; D006207:Half-Life; D006801:Humans; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D052160:Benzothiazoles; D001583:Benzoxazoles; D065692:Cytochrome P-450 CYP3A Inhibitors; D017320:HIV Protease Inhibitors; D051544:Cytochrome P-450 CYP3A; C005465:benzothiazole