IPS-03002

This study investigated the metabolic stability of the casein-derived peptide IPIQY and its active fragments in relation to in vivo hypoglycemic activity. IPIQY dose dependently inhibited DPP-IV activity in Caco-2 cells (IC₅₀ = 73.48 μM). When administered at 300 μmol/kg, IPIQY reduced intestinal and plasma DPP-IV activity by 46.46% and 13.75%, respectively, enhanced plasma insulin levels by 43.42%, and reduced blood glucose levels by 37.77% in OGTT in mice. Metabolic stability results showed IPIQY rapidly entered the bloodstream reaching a peak plasma concentration of 0.51 μM at 2 min after oral administration (300 μmol/kg). It was stable in gastric digestion but degraded into IPIQ and IPI in the intestine. Its low permeability ((4.40 ± 0.18) × 10^-8 cm/s) across Caco-2 cells was mainly due to degradation into IP by BBM. IPI was identified as the most active metabolized fragment. The peptides IPIQY, IPIQ, and IPI, all containing active fragment IPI, exhibited comparable hypoglycemic effects in vivo, whereas IP was significantly less active. Furthermore, the gastrointestinal degradation of IPIQY releases active IPI, contributing to its superior hypoglycemic effect via oral administration compared to intravenous injection. These findings provide new insights into the hypoglycemic potential and administration routes of IPIQY.

Management of type 2 diabetes mellitus (T2DM) using dipeptidyl peptidase IV (DPP IV) inhibitors is gaining precedence as this enzyme plays an indispensable role in cleaving and inactivating peptides, such as glucagon-like peptide-1 (GLP-1), incretin hormones, and glucose-dependent insulinotropic polypeptide (GIP). There are several DPP IV inhibitors used to treat T2DM, but limited by side effects such as disturbed GIT, flu-like symptoms, etc. Thus, there is an urgent need for the development of novel and better DPP IV inhibitors for the management of the same. In the present study, we investigated the effect of new boronic acid-based thiazole compounds as DPP IV inhibitors. We used substituted anilines that were progressively modified through a multi-step synthesis and then chemically characterised. These molecules have good binding affinity and molecular interactions at the active site of the DPP IV enzyme. Two boronic acid-based molecules, i.e. PC06R58 and PC06R108, were used for the assessment of their in-vitro enzymatic activities. Both molecules (PC06108 and PC06R58) exhibited potent uncompetitive DPP IV enzyme inhibition at two different concentrations of 90.9 and 15.6 nM, respectively, compared to sitagliptin having an IC₅₀ of 17.3 nM. Furthermore, the oral glucose tolerance test suggested significantly reduced blood glucose levels at 20 mg/kg of the body weight upon administration of PC06R58 and PC06R108 molecules in rats after glucose ingestion (2 g/kg of the body weight). The compounds showed satisfactory DPP IV inhibition. Furthermore, DPP IV inhibitory activity and acceptable pre-ADME/Tox profile indicate it is a lead compound in this novel class of DPP IV inhibitors.Communicated by Ramaswamy H. Sarma.