title: In vivo pharmacokinetics, metabolism, toxicity, and anti-HIV activity of N'-[2-(2-Thiophene)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (HI-443), a potent non-nucleoside inhibitor of HIV reverse transcriptase.
abstract: N'-[2-(2-Thiophene)ethyl]-N'-[2-(5bromopyridyl)]thiourea (CAS 258340-15-7, HI-443) is a potent non-nucleoside inhibitor of HIV reverse transcriptase (NNRTI) that was rationally designed as a candidate anti-HIV agent. The purpose of the present study was to examine the in vivo pharmacokinetics, metabolism, toxicity, and anti-HIV activity of HI-443. HI-443 was very well tolerated in CD-1 mice and Lewis rats without any detectable toxicity at single parenteral bolus dose levels as high as 80 mg/kg. Intraperitoneally administered HI-443 exhibited anti-HIV activity in the Hu-PBL-SCID mouse surrogate model for hunnan AIDS at a non-toxic daily dose level of 10-20 mg/kg. These preclinical research studies provide the basis for future preclinical studies and clinical development of HI-443 as a new NNRTI candidate.
authors.affiliation: Paradigm Pharmaceuticals, White Bear Lake, MN, USA. faith_uckun@tmo.blackberry.net
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
authors.forename: Heather E
authors.initials: HE
authors.lastname: Tibbles
authors.forename: Taracad K
authors.initials: TK
authors.lastname: Venkatachalam
authors.forename: Douglas
authors.initials: D
authors.lastname: Erbeck
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001772:Blood Cell Count; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D051379:Mice; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D011725:Pyridines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D013890:Thiourea / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D014018:Tissue Distribution