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 RelationshipABSTRACT
High throughput screening of the Roche compound collection led to the identification of diaminopyrroloquinazoline series as a novel class of PTP1B inhibitors. Structural modification of diaminopyrroloquinazoline series resulted in pyrido[2,3-d]pyrimidine-2,4-diamine series which was further optimized to give compounds 5 and 24 as potent, selective (except T-cell phosphatase) PTP1B inhibitors with good mouse PK properties.
Subject(s)
Diamines/pharmacology , Enzyme Inhibitors/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Pyrimidines/pharmacology , Animals , Diamines/chemical synthesis , Diamines/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Humans , Mice , Mice, Inbred C57BL , Molecular Structure , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
In a discovery effort to find safe and effective DGAT-1 inhibitors, we have identified 2-phenyloxazole 4-carboxamide 1 as a conformationally constrained analog of a hydrazide hit, which was previously identified from high-throughput screening. Further optimization of this series has led to chemically more stable 2-phenyloxazole-based DGAT-1 inhibitor 25 with improved solubility, cell-based activity, and pharmacokinetic properties. Compound 25 also demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors , Oxazoles/chemistry , Oxazoles/pharmacology , Administration, Oral , Animals , Body Weight , Diacylglycerol O-Acyltransferase/chemistry , Disease Models, Animal , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Humans , Inhibitory Concentration 50 , Mice , Molecular Structure , Obesity/drug therapy , Oxazoles/therapeutic use , Rats , Solubility , Structure-Activity RelationshipABSTRACT
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 , RatsABSTRACT
New modifications on the C-8 4-aminobenzyl unit of the previously reported 3-alkyl-1,8-dibenzylxanthine inhibitors of cPEPCK are presented. The most active compound reported here is the 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid amide derivative 2 with an IC(50) of 0.29+/-0.08 microM. An X-ray analysis of a heteroaromatic sulfonamide is presented showing a new pi-pi interaction.
Subject(s)
Cytosol/enzymology , Enzyme Inhibitors/pharmacology , Phosphoenolpyruvate Carboxykinase (GTP)/antagonists & inhibitors , Xanthines/pharmacology , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Xanthines/chemistryABSTRACT
A series of N-benzylpyroglutamyl-L-phenylalanine derivatives bearing carbamoyl substituents in the 3- or 4-positions was prepared and assayed for inhibition of the interaction between VCAM and VLA-4. Potent inhibition was observed in a number of analogues with substitution in the 4-position favored over the 3-position. A crystal structure of the key intermediate 25 indicates that it accesses a low energy conformation which closely matches key pharmacophores of a structurally characterized cyclic peptide.
