Discovery of Piragliatin—First Glucokinase Activator Studied in Type 2 Diabetic Patients

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.

Comparison of the Circulating Metabolite Profile of PF-04991532, a Hepatoselective Glucokinase Activator, Across Preclinical Species and Humans: Potential Implications in Metabolites in Safety Testing Assessment

“…It is noteworthy to point out that hydroxylation at either the C-2 and/or C-3 position of the cyclopentyl ring in PF-04991532 and compound 3 will result in the conversion of the prochiral methine at C-1 into a chiral carbon atom and lead to the formation of diastereomeric products. Our present study as well as the one from Sarabu et al (2012) characterized three metabolites derived from cyclopentyl ring oxidation. In theory, single site oxidations on the C-2 or the C-3 positions on the cyclopentyl ring could potentially lead to the formation of eight diastereomers, as shown in Fig.…”

“…Preliminary insights into the structures of M2a, M2b, and M2c were obtained via comparison of the known metabolic fate of the structurally related glucokinase activator, referred to as compound 3 (Fig. 5), in the publication of Sarabu et al (2012). In liver microsomes, compound 3 was shown to undergo monohydroxylations on the C-2 and C-3 positions on the cyclopentyl group, generating the corresponding alcohol regioisomers (Sarabu et al, 2012).…”

“…5), in the publication of Sarabu et al (2012). In liver microsomes, compound 3 was shown to undergo monohydroxylations on the C-2 and C-3 positions on the cyclopentyl group, generating the corresponding alcohol regioisomers (Sarabu et al, 2012). It is noteworthy to point out that hydroxylation at either the C-2 and/or C-3 position of the cyclopentyl ring in PF-04991532 and compound 3 will result in the conversion of the prochiral methine at C-1 into a chiral carbon atom and lead to the formation of diastereomeric products.…”

“…The therapeutic benefits of GK activators in the treatment of type 2 diabetes mellitus (T2DM) have been reviewed (Matschinsky et al, 2011;Sarabu et al, 2011). Early clinical experience with GK activators indicated significant improvements in glycemic control but with an increased risk of hypoglycemia due to excessive GK activation in the pancreas, which resulted in increased insulin secretion at inappropriately low glucose levels (Grimsby et al, 2003;Coghlan and Leighton, 2008;Haynes et al, 2010;Meininger et al, 2011;Sarabu et al, 2012;Pfefferkorn, 2013). To mitigate this hypoglycemia risk, several approaches have been reported to limit GK activation to the liver (Pfefferkorn, 2013).…”

Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease

“…In addition, GK inactivity or over--expression disturbs glucose uptake and has been shown to be defective in T2D patients [90,91]. In addition, GK activation has been recognized as a treatment strategy for T2D and targeted pharmacologically by GK activating chemical compounds such as piragliatin, leading to decreased hepatic glucose output in T2D patients [92]. As BAD is phosphorylated in an AKAP--dependent manner by PKA, targeting the PKA--WAVE--1 interaction within the protein complex potentially induces more BAD activity and thus ultimately increases GK activity.…”