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

Summary

N'-[2- (2-Thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea (CAS 258340-15-7, HI-443) is a potent non-nucleoslde 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 human 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.

Key words

AIDS - Anti-HIV agents - CAS 258340-15-7 - HI-443, pharmacokinetics - Human immunodeficiency virus - Non-nucleoside reverse transcriptase inhibitors - N'-[2-(2-Thiophene)ethyl]-N'-[2-(5-bromopyridyl)]thiourea