Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents.
Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.
Ahmad
Saleem
S
Research & Development, Bristol-Myers Squibb Co, PO Box 4000, Princeton, NJ 08543, United States. saleem.ahmad@bms.com
Ngu
Khehyong
K
Miller
Keith J
KJ
Wu
Ginger
G
Hung
Chen-pin
CP
Malmstrom
Sarah
S
Zhang
Ge
G
O'Tanyi
Eva
E
Keim
William J
WJ
Cullen
Mary Jane
MJ
Rohrbach
Kenneth W
KW
Thomas
Michael
M
Ung
Thao
T
Qu
Qinling
Q
Gan
Jinping
J
Narayanan
Rangaraj
R
Pelleymounter
Mary Ann
MA
Robl
Jeffrey A
JA
D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D004435:Eating / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D052999:Quinazolinones / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism
D019440:Anti-Obesity Agents; D052999:Quinazolinones; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists