Improved oral bioavailability of anti-HIV agent N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (HI-443) in a novel lipophilic formulation.
N'-[2-(2-Thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (CAS 258340-15-7, HI-443) is a rationally designed non-nucleoside reverse transcriptase inhibitor (NNRTI) with potent anti-HIV activity at nanomolar concentrations but poor oral bioavailability. Here the identification of a novel oleic acid containing lead formulation of HI-443 is described which resulted in a approximately 10-fold improvement of its oral bioavailability yielding 10-fold higher systemic exposure levels in mice. Formulated HI-443 exhibited a favorable pharmacokinetics and toxicity profile in mice.
Uckun
Fatih M
FM
Paradigm Pharmaceuticals, 2139 Fourth Street, White Bear Lake, MN 55110, USA. fatih_uckun@tmo.blackberry.net
Erbeck
Douglas
D
Tibbles
Heather
H
Qazi
Sanjive
S
Venkatachalam
Taracad K
TK
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001772:Blood Cell Count; D002626:Chemistry, Pharmaceutical; D005079:Excipients; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity
D005079:Excipients; C403248:HI 443; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D013890:Thiourea