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Updated: May 20, 2026

A High-content In Vitro Pancreatic Islet β-cell Replication Discovery Platform
Published on: July 16, 2016
Discovery of piragliatin--first glucokinase activator studied in type 2 diabetic patients
Ramakanth Sarabu1, Fred T Bizzarro, Wendy L Corbett
1Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, DTA Metabolism, 340 Kingsland Street, Nutley, New Jersey 07110, United States. ramakanth.sarabu@roche.com
Abstract:
Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase β-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.
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