Synthesis of functionalized 1,8-naphthyridinones and their evaluation as novel, orally active CB1 receptor inverse agonists

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 3, 2006, Pages 681-685

  Debenham, John S ^a   Madsen Duggan, Christina B ^a   Walsh, Thomas F ^a   Wang, Junying ^a   Tong, Xinchun ^a   Doss, George A ^a   Lao, Julie ^a   Fong, Tung M ^a   Schaeffer, Marie Therese ^a   Xiao, Jing Chen ^a   Huang, Cathy R R C ^a   Shen, Chun Pyn ^a   Feng, Yue ^a   Marsh, Donald J ^a   Stribling, D Sloan ^a   Shearman, Lauren P ^a   Strack, Alison M ^a   MacIntyre, D Euan ^a   Van Der Ploeg, Lex H T ^a   Goulet, Mark T ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Anorexigenic; Cannabinoid; CB1; CB2; Inverse agonist; Obesity

Indexed keywords

1,8 NAPHTHYRIDINONE; CANNABINOID 1 RECEPTOR; CANNABINOID RECEPTOR ANTAGONIST; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; CONTROLLED STUDY; DRUG EFFICACY; DRUG RECEPTOR BINDING; DRUG SCREENING; DRUG SYNTHESIS; EVALUATION; FOOD INTAKE; KNOCKOUT MOUSE; MALE; MOUSE; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; BINDING SITES; EATING; MICE; MICE, KNOCKOUT; MODELS, CHEMICAL; NAPHTHYRIDINES; RECEPTOR, CANNABINOID, CB1;

ANIMALIA;

EID: 29544438244     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.10.028     Document Type: Article

References (17)

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14. The calculated log D for this compound is 3.1 (Advanced Chemistry Development Log D software version 6).
15. Food intake assay protocol: compounds were solubilized in 10% Tween 80 in water. DIO Sprague-Dawley rats were dosed PO (orally) 30-60 min before dark onset. There were six rats in each treatment group. Food cups for each cage were weighed every 5 min to measure food consumption (in an automated food intake system) during the 18 h period following dosing with test compounds. Overnight body weight changes were also measured.
16. C57BL/6 mice were purchased from Taconic Farms. Cnr1 knockout mice were generated by the laboratory of Dr. Andreas Zimmer, National Institute of Mental Health, NIH (A. Zimmer, A.M. Zimmer, A.G. Hohmann, M. Herkenham, and T.I. Bonner Proc. Natl. Acad. Sci. 96 1999 5780 )and generously provided by him.
17. In support of the knockout mice study, 14 was first evaluated in C57BL/6 wild-type mice. Ad libitum fed 12-week-old male mice (n = 12 per group) were dosed orally with 14 at 1, 3, or 10 mpk in a 0.225% methylcellulose/10% Tween 80 vehicle ∼30 min prior to dark phase of the light cycle. At the highest dose, 14 significantly (P < 0.0001) inhibited 2 h food intake (∼49% reduction), overnight food intake (∼40% reduction), and overnight (18 h) gains in body weight (∼143% reduction).