Antidiabetic Effect of JP-2266, a Novel SGLT1/2 Dual Inhibitor, for the Treatment of Type 1 Diabetes

Abstract

JP-2266, a potent, a new synthetic small molecule, is highly selective sodium glucose cotransporter (SGLT) 1 and 2 inhibitor, and offers new therapeutic regimen by improving glycemic control for type 1 diabetes mellitus (T1DM). Insulin used for blood glucose lowering, which is an important agent in controlling blood glucose in T1DM patients, however, it is not easy to be administrated due to inconvenience of injection and hypoglycemic risk. JP-2266, as adjunct therapy to insulin, is expected to overcome the shortcomings of insulin monotherapy in T1DM. We discovered JP-2266, a preclinical candidate to develop as an agent for the treatment of type 1 diabetes. IC50 values of JP-2266 were 10.1 nM and 1.3 nM, respectively, for SGLT1 and SGLT2 in vitro glucose uptake assay. Sotagliflozin which is known as a SGLT1 and 2 dual inhibitor was 36 nM and 1.8 nM, respectively, in vitro glucose uptake assay. Also JP-2266 showed a significant decrease postprandial blood glucose level in type 1 diabetes rat models. When JP-2266 was treated with 1, 2, or 5 mg/kg by single oral administration in streptozotocin (STZ)-induced T1DM rat model, AUC0-4h (mg·h/dL) for 4 hours in OGTT was 38.4%, 48.1% and 56.4%, respectively, compared to vehicle treated group. Moreover, STZ rats treated with 5mg/kg of JP-2266 showed the same AUC0-4h reduction rate as the high-dose insulin treated group (1.8U/kg), and blood glucose reduction rate of JP-2266 and Sotagliflozin at 10 mg/kg was 49.4% and 39.1%, respectively, compared to vehicle treated group in oral repeated administration for 28 days. Additionally, HbA1c of JP-2266 treated group was 6.4%, while Sotagliflozin treated group was 7.2% at 10 mg/kg. We suggest that JP-2266 will be a potent candidate agent for the treatment of T1DM, since JP-2266 has a more potent reducing effect on hyperglycemia in OGTT and showed comparable effect by oral repeated dose administration than those of Sotagliflozin. Disclosure Y. Park: None.