A New Class of GLP-1 Analog, SKL-18287; Pharmacological Profiles
Conference: American Diabetes Association 70th Scientific Sessions Poster presentation P-586
First generation GLP-1 analogs, exenatide and liraglutide have been launched as treatment for T2DM. But they require daily injection for patients. Therefore the development of 2nd-generation GLP-1 analogs, LAR, which have better pharmacological and pharmacokinetic profiles is underway, to give more effective benefits to patients. SKL-18287 (hereafter “SKL”) is designed to have DPP-IV resistance and plasma protein binding ability. SKL is a novel GLP-1 analog that modifies native GLP-1 with several natural amino acids without any chemical modifications and is currently developed as a sustained release product. The pharmacological profiles of SKL using various models were investigated. 1) SKL exhibited strong stability when co-incubated with rat plasma in vitro, and more than 80% of SKL persisted after 48 hr incubation. 2) In mouse insulinoma cell line, MIN6, SKL increased glucose stimulated insulin secretion in a concentration dependent manner. The maximum increment of SKL (92%) was comparable to that of native GLP-1 (100%). 3) The blood glucose lowering effect in the glucose tolerance test (ipGTT) of C57BL/6J mice was investigated. The single subcutaneously injected SKL (1, 3 nmol/kg) reduced 48-57% of area under the blood glucose - time curve (AUC0-60min) (exendin 4, or “Ex4” [0.06 nmol/kg]: 55%, all p<0.01 vs. vehicle as 100%). Moreover SKL exhibited a similar blood glucose lowering effect in the second challenge of ipGTT at 3 hr after the first ipGTT, whereas Ex4 did not (AUC0-60min: SKL: 46 -54%; p<0.01 vs. vehicle, Ex4: 10%; ns). In other word, the effect of SKL was sustained longer than that of Ex4. 4) The blood glucose lowering effect of SKL on the random fed state of db/db mice was investigated. In this model, SKL also exhibited an excellent blood glucose lowering effect with dose dependent manner up to 5 hr after a single subcutaneous injection. In conclusion, these results indicated that SKL is expected to be more effective than existing GLP-1 analogs. Additionally, considering its structural, pharmacokinetic, and ease manufacturing characteristics, we believe that SKL has a potential impact as a new class of GLP-1 analog.
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