Anagliptin, a potent dipeptidyl peptidase IV inhibitor: its single-crystal structure and enzyme interactions.

The single-crystal structure of anagliptin, N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide, was determined. Two independent molecules were held together by intermolecular hydrogen bonds, and the absolute configuration of the 2-cyanopyrrolidine ring delivered from l-prolinamide was confirmed to be S. The interactions of anagliptin with DPP-4 were clarified by the co-crystal structure solved at 2.

Synthesis and pharmacological characterization of potent, selective, and orally bioavailable isoindoline class dipeptidyl peptidase IV inhibitors.

Focused structure-activity relationships of isoindoline class DPP-IV inhibitors have led to the discovery of 4b as a highly selective, potent inhibitor of DPP-IV. In vivo studies in Wistar/ST rats showed that 4b was converted into the strongly active metabolite 4l in high yield, resulting in good in vivo efficacy for antihyperglycemic activity.

Discovery and pharmacological characterization of N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (anagliptin hydrochloride salt) as a potent and selective DPP-IV inhibitor.

In the course of our program for discovery of novel DPP-IV inhibitors, a series of pyrazolo[1,5-a]pyrimidines were found to be novel DPP-IV inhibitors. We identified N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (4a) and described its pharmacological profiles.

Change in blood kinin and plasma porcine pancreatic kallikrein concentrations after oral administration of kallikrein formulation in dog.

Oral formulation of tissue kallikrein consists primarily of porcine pancreatic kallikrein (PPK) and is used to improve peripheral circulation, menopausal symptoms, and impaired chorioretinal circulation. Although gastrointestinal absorption of tissue kallikrein after oral administration has been reported in nonclinical and clinical studies, the increase in the concentration of pharmacologically active kinins, which are produced from kininogens by tissue kallikrein, has not been investigated. In this study, kallikrein formulation was orally administered to dogs and an increase in PPK in plasma was confirmed, along with an increase in the blood kinin level.

Tissue kallikrein inhibits retinal neovascularization via the cleavage of vascular endothelial growth factor-165.

Objective: Tissue kallikrein, a widely used vasodilator for the treatment of hypertension and peripheral circulatory disorder, acts by releasing kinin, a potent vasodilator peptide. To identify the role of tissue kallikrein in retinal neovascularization, we investigated the antiangiogenic effect by using an in vitro and in vivo angiogenesis model.

Methods And Results: Tissue kallikrein in vitreous fluid was markedly elevated in proliferative diabetic retinopathy patients compared with that in control patients with macular hole and epiretinal membrane.