A thienopyridazinone-based melanin-concentrating hormone receptor 1 antagonist with potent in vivo anorectic properties.
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.
Dyck
Brian
B
Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, California 92130, USA. bdyck@neurocrine.com
Markison
Stacy
S
Zhao
Liren
L
Tamiya
Junko
J
Grey
Jonathan
J
Rowbottom
Martin W
MW
Zhang
Mingzhu
M
Vickers
Troy
T
Sorensen
Katie
K
Norton
Christi
C
Wen
Jenny
J
Heise
Christopher E
CE
Saunders
John
J
Conlon
Paul
P
Madan
Ajay
A
Schwarz
David
D
Goodfellow
Val S
VS
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
D001067:Appetite Depressants; C491208:MCHR1 protein, rat; D011724:Pyridazines; D017481:Receptors, Somatostatin; D013876:Thiophenes; C062482:pyridazine