Constitutive increase in active GLP-1 levels by the DPP4 inhibitor ASP4000 on a new meal tolerance test in Zucker fatty rats.

Glucagon-like peptide-1 (GLP-1), an incretin hormone, is essential for the regulation of insulin secretion and glucose homeostasis. GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP4); therefore, DPP4 inhibitors are considered to be a novel class of oral antihyperglycemic agents. These agents are currently under development as treatments for type 2 diabetes.

ASP4000, a slow-binding dipeptidyl peptidase 4 inhibitor, has antihyperglycemic activity of long duration in Zucker fatty rats.

ASP4000 ((2S)-1-{[(1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride) is a novel, potent and selective dipeptidyl peptidase 4 (DPP IV, EC 3.

ASP4,000, a novel, selective, dipeptidyl peptidase 4 inhibitor with antihyperglycemic activity.

ASP4,000, (2S)-1-{[(1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecar bonitrile hydrochloride, is a novel dipeptidyl peptidase (DPP) 4 inhibitor.

Acute and chronic effects of FR-149175, a beta 3-adrenergic receptor agonist, on energy expenditure in Zucker fatty rats.

Clinical therapies for both obesity and obese non-insulin-dependent diabetes mellitus require maintenance of reduced body weight after the initial successful reduction resulting from calorie control, exercise, or medication. Although beta(3)-adrenergic receptor (beta(3)-AR) agonists have been shown to stimulate whole body energy expenditure and lipid mobilization, whether stimulatory effects on oxygen consumption and lipolysis are influenced by chronic exposure to agonists has not been fully characterized. We therefore examined the acute and chronic effects of FR-149175, a selective beta(3)-AR agonist, on whole body oxygen consumption in genetically obese Zucker fatty rats.

Novel potent antagonists of human neuropeptide Y Y5 receptors. Part 3: 7-methoxy-1-hydroxy-1-substituted tetraline derivatives.

As a part of our continuing research on NPY-Y5 receptor antagonists in the series of novel 6-methoxybenzo[a]cycloheptene derivatives, we discovered a novel skeleton, 7-methoxy-1-hydroxytetraline 7 which had been used as an intermediate, to be more suitable for increasing potencies leading to compound 3 (FR230481). Additionally, we discovered that the naphthalenesulfonamide moiety which was thought to be an essential pharmacophore could be replaced by the 5-chlorobenzothiazolin-3-acetic acid moiety to lead to potent compound 4 (FR233118). The structure-activity relationships on compounds 3,4 and their related derivatives are described.

Novel potent antagonists of human neuropeptide Y Y5 receptors. Part 2: substituted benzo[a]cycloheptene derivatives.

Novel benzo[a]cycloheptene derivatives were prepared for the purpose of searching new neuropeptide Y-Y5 (NPY-Y5) receptor antagonists. The structure-activity relationships are described and compound 2o (FR226928) showed the most potent affinity for Y5 receptor of all we prepared and was found to have higher potency and better selectivity for Y5 over Y1 receptor affinities when compared with the known lead compound 1.