Linagliptin, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.
Boehringer Ingelheim Corp is developing the novel, xanthine-based dipeptidyl peptidase (DPP)-4 inhibitor linagliptin for the potential treatment of type 2 diabetes mellitus. In vitro assays suggested that linagliptin was a potent DPP-4 inhibitor, with good selectivity for DPP-4 compared with other DPPs and proteases. The inhibition of DPP-4 by linagliptin was also demonstrated in vivo, resulting in increased glucagon-like peptide 1 levels and improved glucose tolerance in both healthy animals and models of disease. Furthermore, linagliptin exhibited prolonged pharmacodynamic activity, with long-lasting DPP-4 inhibition across different species. The prolonged DPP-4 inhibition observed in preclinical models has translated to humans; linagliptin demonstrated approximately 80% inhibition of DPP-4 activity at daily doses as low as 5 mg in phase II clinical trials. The effects were sustained, and no signs or symptoms of hypoglycemia were observed, even at high doses of up to 600 mg. The low therapeutic dose of linagliptin, the long-lasting inhibition of DPP-4 activity and the good safety/tolerability profile exhibited thus far suggest that linagliptin may be superior to competitors. The results from ongoing phase III clinical trials will provide further information on such aspects; however, from the available data, linagliptin appears to have promise for market success.
Tiwari
Atul
A
Jubilant Biosys Ltd, Drug Discovery Unit, #96, 2nd Stage, Industrial Suburb Yeshwantpur, Bangalore 560022, India. atul_tiwari@jubilantbiosys.com
D000818:Animals; D018849:Controlled Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000069476:Linagliptin; D011687:Purines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D013045:Species Specificity
D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin