ro-28-1675 and Diabetes-Mellitus--Type-2

ro-28-1675 has been researched along with Diabetes-Mellitus--Type-2* in 2 studies

Other Studies

2 other study(ies) available for ro-28-1675 and Diabetes-Mellitus--Type-2

Article	Year
Discovery of piragliatin--first glucokinase activator studied in type 2 diabetic patients. Journal of medicinal chemistry, 2012, Aug-23, Volume: 55, Issue:16 Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase β-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D. Topics: Animals; Benzeneacetamides; Diabetes Mellitus, Type 2; Dogs; Enzyme Activators; Female; Glucokinase; Glucose; Humans; Hypoglycemic Agents; Lipidoses; Liver; Macaca fascicularis; Male; Mice; Mice, Inbred C57BL; Postprandial Period; Rabbits; Rats; Rats, Wistar; Stereoisomerism; Structure-Activity Relationship	2012
Discovery, structure-activity relationships, pharmacokinetics, and efficacy of glucokinase activator (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (RO0281675). Journal of medicinal chemistry, 2010, May-13, Volume: 53, Issue:9 Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SAR development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described. Compound 21a (RO0281675) was used to validate the clinical relevance of targeting GK to treat type 2 diabetes. Topics: Animals; Blood Glucose; Cell Line; Cytotoxins; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Discovery; Glucokinase; Humans; Hypoglycemic Agents; Insulin; Male; Mice; Pharmacokinetics; Structure-Activity Relationship; Sulfones; Thiazoles	2010

Article

Year

Discovery of piragliatin--first glucokinase activator studied in type 2 diabetic patients.

Journal of medicinal chemistry, 2012, Aug-23, Volume: 55, Issue:16

Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase β-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.

Topics: Animals; Benzeneacetamides; Diabetes Mellitus, Type 2; Dogs; Enzyme Activators; Female; Glucokinase; Glucose; Humans; Hypoglycemic Agents; Lipidoses; Liver; Macaca fascicularis; Male; Mice; Mice, Inbred C57BL; Postprandial Period; Rabbits; Rats; Rats, Wistar; Stereoisomerism; Structure-Activity Relationship

2012

Discovery, structure-activity relationships, pharmacokinetics, and efficacy of glucokinase activator (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (RO0281675).

Journal of medicinal chemistry, 2010, May-13, Volume: 53, Issue:9

Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SAR development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described. Compound 21a (RO0281675) was used to validate the clinical relevance of targeting GK to treat type 2 diabetes.

Topics: Animals; Blood Glucose; Cell Line; Cytotoxins; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Discovery; Glucokinase; Humans; Hypoglycemic Agents; Insulin; Male; Mice; Pharmacokinetics; Structure-Activity Relationship; Sulfones; Thiazoles

2010