Discovery of novel diarylketoxime derivatives as selective and orally active melanin-concentrating hormone 1 receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 18, 2009, Pages 5339-5345

  Suzuki, Takao ^a   Kameda, Minoru ^a   Ando, Makoto ^a   Miyazoe, Hiroshi ^a   Sekino, Etsuko ^a   Ito, Satoru ^a   Masutani, Kouta ^a   Kamijo, Kaori ^a   Takezawa, Akihiro ^a   Moriya, Minoru ^a   Ito, Masahiko ^a   Ito, Junko ^a   Nakase, Kazuho ^a   Matsushita, Hiroko ^a   Ishihara, Akane ^a   Takenaga, Norihiro ^a   Tokita, Shigeru ^a   Kanatani, Akio ^a   Sato, Nagaaki ^a   Fukami, Takehiro ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Antagonist; Melanin concentrating hormone 1 receptor; Obesity; Oxime

Indexed keywords

MELANIN CONCENTRATING HORMONE RECEPTOR 1 ANTAGONIST; OXIME DERIVATIVE; POTASSIUM CHANNEL HERG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DRUG ACTIVITY; DRUG DOSE COMPARISON; DRUG STRUCTURE; DRUG SYNTHESIS; MOUSE; NONHUMAN; OBESITY; RAT; STRUCTURE ACTIVITY RELATION; WEIGHT REDUCTION;

ANIMALS; ANTI-OBESITY AGENTS; BODY WEIGHT; ETHER-A-GO-GO POTASSIUM CHANNELS; HUMANS; MICE; MICE, INBRED C57BL; OBESITY; OXIMES; PROTEIN BINDING; RECEPTORS, SOMATOSTATIN; STRUCTURE-ACTIVITY RELATIONSHIP;

MUS;

EID: 68949108015     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.07.132     Document Type: Article

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44. Male C57BL/6J mice (CLEA Japan, Tokyo, Japan) were used. Mice were housed individually in plastic cages under controlled temperature and humidity (23 ± 2 °C, 55 ± 15%), and a 12-h light-dark cycle (lights on 7:00-19:00). The mice were fed a moderately high-fat (MHF) diet (Oriental BioService Kanto, Ibaraki, Japan; 52.4% energy as carbohydrate, 15.0% as protein and 32.6% as fat, 4.4 kcal/g) for about 6 months before the experiment. Mice had ad libitum access to tap water. The mice were divided into 3 groups to match averaged body weight, and each group was orally administered either vehicle or the MCH-1R antagonist at doses of 10 mg/kg, b.i.d. or 30 mg/kg, q.d. for 13 days (n = 7-9). Drugs were administered only on weekdays. Drug administration was done about 1 h after lights-on (morning) and about 1 h before lights-off (evening), and measurement of body weight was done just before the evening drug administration. In the vehicle- and 30 mg/kg, q.d.-treated groups, mice were treated with vehicle at the morning administration. All experimental procedures were approved by the Institutional Animal Care and Use Committee.