ABSTRACT
Melanin-concentrating hormone receptor antagonists containing thieno- and a benzopyridazinone cores were designed and tested as potential anorectic agents. These ligands showed high affinity for the receptor, potent functional activity in vitro, and good oral bioavailabilty in rats. The thiophene analogue exhibited low iv clearance, long half-life, and high brain penetration. In obese rats, the thienopyridazinone demonstrated a dose-dependent reduction in feeding and body weight with doses between 1 and 10 mg kg-1.
Subject(s)
Appetite Depressants/chemical synthesis , Pyridazines/chemical synthesis , Receptors, Somatostatin/antagonists & inhibitors , Thiophenes/chemical synthesis , Animals , Appetite Depressants/pharmacokinetics , Appetite Depressants/pharmacology , Biological Availability , Body Weight/drug effects , Brain/metabolism , Eating/drug effects , Half-Life , Male , Obesity/drug therapy , Permeability , Pyridazines/chemistry , Pyridazines/pharmacology , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Thiophenes/pharmacokinetics , Thiophenes/pharmacologyABSTRACT
A series of substituted chromones were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor 1. Compounds with subnanomolar binding affinity and 66% oral bioavailability in rats were discovered.
