title: A thienopyridazinone-based melanin-concentrating hormone receptor 1 antagonist with potent in vivo anorectic properties.
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.
authors.affiliation: Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, California 92130, USA. bdyck@neurocrine.com
authors.forename: Brian
authors.initials: B
authors.lastname: Dyck
authors.forename: Stacy
authors.initials: S
authors.lastname: Markison
authors.forename: Liren
authors.initials: L
authors.lastname: Zhao
authors.forename: Junko
authors.initials: J
authors.lastname: Tamiya
authors.forename: Jonathan
authors.initials: J
authors.lastname: Grey
authors.forename: Martin W
authors.initials: MW
authors.lastname: Rowbottom
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Zhang
authors.forename: Troy
authors.initials: T
authors.lastname: Vickers
authors.forename: Katie
authors.initials: K
authors.lastname: Sorensen
authors.forename: Christi
authors.initials: C
authors.lastname: Norton
authors.forename: Jenny
authors.initials: J
authors.lastname: Wen
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Heise
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Paul
authors.initials: P
authors.lastname: Conlon
authors.forename: Ajay
authors.initials: A
authors.lastname: Madan
authors.forename: David
authors.initials: D
authors.lastname: Schwarz
authors.forename: Val S
authors.initials: VS
authors.lastname: Goodfellow
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D006207:Half-Life; D008297:Male; D009765:Obesity / Q000188:drug therapy; D010539:Permeability; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D001067:Appetite Depressants; C491208:MCHR1 protein, rat; D011724:Pyridazines; D017481:Receptors, Somatostatin; D013876:Thiophenes; C062482:pyridazine