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1.
Bioorg Med Chem Lett ; 23(10): 2936-40, 2013 May 15.
Article in English | MEDLINE | ID: mdl-23582275

ABSTRACT

Glycogen synthase (GS) catalyzes the transfer of glucose residues from UDP-glucose to a glycogen polymer chain, a critical step for glucose storage. Patients with type 2 diabetes normally exhibit low glycogen levels and decreased muscle glucose uptake is the major defect in whole body glucose disposal. Therefore, activating GS may provide a potential approach for the treatment of type 2 diabetes. In order to identify non-carboxylic acids GS activators, we designed and synthesized a series of 2-N-alkyl- and 2-N-aryl-indazolone derivatives and studied their activity in activating human GS.


Subject(s)
Drug Design , Enzyme Inhibitors/pharmacology , Glycogen Synthase/antagonists & inhibitors , Indazoles/pharmacology , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , Glycogen Synthase/metabolism , Indazoles/administration & dosage , Indazoles/chemical synthesis , Mice , Mice, Inbred C57BL , Molecular Structure , Structure-Activity Relationship
2.
J Med Chem ; 54(7): 2433-46, 2011 Apr 14.
Article in English | MEDLINE | ID: mdl-21413799

ABSTRACT

Diacylglycerol acyltransferase-1 (DGAT-1) is the enzyme that catalyzes the final and committed step of triglyceride formation, namely, the acylation of diacylglycerol with acyl coenzyme A. DGAT-1 deficient mice demonstrate resistance to weight gain on high fat diet, improved insulin sensitivity, and reduced liver triglyceride content. Inhibition of DGAT-1 thus represents a potential novel approach for the treatment of obesity, dyslipidemia, and metabolic syndrome. In this communication, we report the identification of the lead structure 6 and our lead optimization efforts culminating in the discovery of potent, selective, and orally efficacious carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxamides. In particular, compound 29 (DGAT-1 enzyme assay, IC(50) = 57 nM; CHO-K1 cell triglyceride formation assay, EC(50) = 0.5 µM) demonstrated dose dependent inhibition of weight gain in diet induced obese (DIO) rats (0.3, 1, and 3 mg/kg, p.o., qd) during a 21-day efficacy study. Furthermore, compound 29 demonstrated improved glucose tolerance determined by an oral glucose tolerance test (OGTT).


Subject(s)
Amides/chemistry , Amides/pharmacology , Carboxylic Acids/chemistry , Diabetes Mellitus/drug therapy , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Drug Discovery , Obesity/drug therapy , Oxazoles/chemistry , Oxazoles/pharmacology , Administration, Oral , Amides/administration & dosage , Amides/pharmacokinetics , Animals , Cell Line , Diabetes Mellitus/enzymology , Dogs , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Inhibitory Concentration 50 , Male , Mice , Obesity/enzymology , Oxazoles/administration & dosage , Oxazoles/pharmacokinetics , Rats
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