2012
DOI: 10.1021/jm3008689
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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, l… Show more

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Cited by 86 publications
(95 citation statements)
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“…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.…”
Section: Circulating Metabolites Of Pf-04991532mentioning
confidence: 64%
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“…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.…”
Section: Circulating Metabolites Of Pf-04991532mentioning
confidence: 64%
“…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).…”
Section: Circulating Metabolites Of Pf-04991532mentioning
confidence: 99%
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“…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.…”
Section: Akaps In Glucose Homeostasis and Obesitymentioning
confidence: 99%