Design and synthesis of a new class of malonyl-CoA decarboxylase inhibitors with anti-obesity and anti-diabetic activities

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 20, 2010, Pages 6088-6092

  Tang, Haifeng ^a   Yan, Yan ^a   Feng, Zhe ^a   De Jesus, Reynalda K ^a   Yang, Lihu ^a   Levorse, Dorothy A ^a   Owens, Karen A ^a   Akiyama, Taro E ^a   Bergeron, Raynald ^a   Castriota, Gino A ^a   Doebber, Thomas W ^a   Ellsworth, Kenneth P ^a   Lassman, Michael E ^a   Li, Cai ^a   Wu, Margaret S ^a   Zhang, Bei B ^a   Chapman, Kevin T ^a   Mills, Sander G ^a   Berger, Joel P ^a   Pasternak, Alexander ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Acetyl CoA; Acetyl CoA carboxylase (ACC); Diabetes; Fatty acid oxidation (FAO); Fatty acid synthase (FAS); Glucose oxidation; Malonyl CoA; Malonyl CoA decarboxylase (MCD); Obesity

Indexed keywords

2 AMINOTHIOAZOLE; CARBOXYLIC ACID DERIVATIVE; DECARBOXYLASE INHIBITOR; GLUCOSE; MALONYL COENZYME A DECARBOXYLASE INHIBIBITOR; PIPERAZINE; PIPERAZINE DERIVATIVE; PIPERIDINE DERIVATIVE; PYRROLE DERIVATIVE; SULFONE; TETRAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BODY WEIGHT; CONTROLLED STUDY; DOSE RESPONSE; DRUG DESIGN; DRUG EFFICACY; DRUG PENETRATION; DRUG POTENCY; DRUG SCREENING; DRUG SYNTHESIS; FOOD INTAKE; GLUCOSE BLOOD LEVEL; IC 50; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION;

ANIMALS; ANTI-OBESITY AGENTS; BLOOD GLUCOSE; BODY WEIGHT; CARBOXY-LYASES; DIABETES MELLITUS, TYPE 2; DRUG DESIGN; EATING; HUMANS; HYPOGLYCEMIC AGENTS; MICE; MICE, INBRED C57BL; OBESITY; PROPANOLS; THIAZOLES;

MURINAE; MUS;

EID: 77956905089     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.08.047     Document Type: Article

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18. SAR study of 3 on the phenyl ring led to significant improvement in enzyme inhibition potency. These results will be reported in a separate communication.
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20. Analogs substituted with other aromatic rings were also synthesized, but are generally less potent than their phenyl analogs.
21. Compound 10a was prepared from direct nucleophilic substitution of commercially available 4-hydroxy-4-phenylpiperidine to bromide 14.
22. Compounds of interest were incubated with primary db/db mouse hepatocytes for 30 min. Malonyl-CoA levels were then measured to assess their ability to inhibit whole cell MCD activity.
23. Plasma/brain drug levels at 30 mpk 4 h after po dosing in mice: 7w plasma 2.38 μM, brain 0.08 μM; 7y plasma 20.5 μM, brain 0.79 μM.
24. Plasma/brain drug levels for 10d at 30 mpk 4 h after po dosing in mice: plasma 15.8 μM, brain 5.4 μM.
25. The levels of malonyl-CoA in the collected hypothalami were quantified by HPLC with known internal standard.
26. Assay protocol: db/db mice were orally dosed with compounds or vehicle in 0.5% methylcellulose 5 h after food was removed. Two hours later blood samples were obtained by the tail vein. Plasma glucose and β-HBA levels of mice dosed with compounds and vehicle were assayed. Percent correction of glucose and percent decrease in β-HBA of the compounds were calculated versus vehicle control.