Discovery of a novel phenylethyl benzamide glucokinase activator for the treatment of type 2 diabetes mellitus

Park, Kaapjoo; Lee, Byoung Moon; Kim, Young Hwan; Han, Taedong; Yi, Wonhui; Lee, Dong Hoon; Choi, Hyun Ho; Chong, Wonee; Lee, Chun Ho

doi:10.1016/j.bmcl.2012.11.018

Cited by 30 publications

(13 citation statements)

References 18 publications

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“…Effective measures to control fasting and postprandial glucose levels are imperative in the management of DM. Though, several oral hypoglycemic drugs are currently available, their prolonged consumption produces adverse side effects (Park et al, 2013). Hence, researchers are investigating the management of diabetes and its complications through phytochemicals, due to their natural abundance, efficacy, lesser side effects and cultural acceptability (Kasetti et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

β-Caryophyllene, a natural sesquiterpene, modulates carbohydrate metabolism in streptozotocin-induced diabetic rats

Basha

Sankaranarayanan

2014

Acta Histochemica

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Section: Introductionmentioning

confidence: 99%

β-Caryophyllene, a natural sesquiterpene, modulates carbohydrate metabolism in streptozotocin-induced diabetic rats

Basha

Sankaranarayanan

2014

Acta Histochemica

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“…GK activators are the novel category of therapeutic agents which activate GK allosterically and demonstrate their hypoglycaemic potential (Coghlan & Leighton, 2008;Matschinsky et al, 2011;Pal, 2009a;Perseghin, 2010). A broad variety of chemically different classes of compounds including substituted benzamide analogues (Charaya, Pandita, Grewal, & Lather, 2018;Iino et al, 2010;Li et al, 2011;Mao et al, 2012;Pike et al, 2011;Park et al, 2014Park et al, , 2013Singh et al, 2016;Wang et al, 2017;Zhang, Chen, et al, 2012), carboxamide derivatives such as acetamides, butanamides and other (Cheruvallath et al, 2013;Li et al, 2010;Mitsuya et al, 2009;Pfefferkorn, Tu, et al, 2012;Ye et al, 2012), acrylamides (Sidduri et al, 2010), heterocyclic compounds such as benzimidazole derivatives (Ishikawa et al, 2009;Takahashi et al, 2009), quinazolines derivatives (Iino et al, 2009), thiazole derivatives (Hinklin et al, 2013), pyrimidine derivatives (Filipski et al, 2013), and substituted urea compounds (Li et al, 2014;Zhang, Tian, et al, 2012) were developed recently to act as potent GK activators with antidiabetic effects. Several GK activators had been advanced to phase II clinical trials including piragliatin, AZD6370, AZD1656, MK-0941 and AMG151; although potent reduction of blood glucose efficacy had been reported, possible adverse effects had also been observed, including hypoglycaemia and raised triglyceride levels.…”

Section: Introductionmentioning

confidence: 99%

N‐pyridin‐2‐yl benzamide analogues as allosteric activators of glucokinase: Design, synthesis, in vitro, in silico and in vivo evaluation

et al. 2018

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Glucokinase (GK) is the key enzyme controlling levels of blood glucose under normal physiological range, and GK activators are emerging class of drug candidates with promising hypoglycaemic activity. The current study was planned to design, synthesize and evaluate novel N-pyridin-2-yl benzamide analogues as allosteric activators of GK. A novel series of N-pyridin-2-yl benzamide analogues were synthesized starting from 3-nitrobenzoic acid and evaluated in vitro for GK activation followed by in silico studies to predict the binding interactions of the designed molecules with GK protein. The selected synthesized molecules (compounds 5b, 5c, 5e, 5g, 5h and 6d) which displayed excellent GK activity (GK fold activation around 2) in GK assay and appreciable binding interaction with GK in docking studies were further evaluated for their antihyperglycaemic potential using oral glucose tolerance test (OGTT) in rats. Amongst the compounds tested in vivo (OGTT assay) for antihyperglycaemic potential, compounds 5c, 5e and 5g displayed significant reduction in blood glucose levels. Compound 5e displayed most significant antidiabetic activity and comparable to that of standard drug in animal studies. The N-pyridin-2-yl benzamide analogues discovered in the current study can provide some lead molecules for the development of potent oral GK activators with minimum side-effects for the management of type 2 diabetes. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Grewal AS, Kharb R, Prasad DN, Dua JS, Lather V. N-pyridin-2-yl benzamide analogues as allosteric activators of glucokinase: Design, synthesis, in vitro, in silico and in vivo evaluation. Chem Biol Drug Des. 2019;93:364-372.

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“…GK activators are the new class of drug candidates which act on GK enzyme and show their hypoglycemic activity (Coghlan and Leighton, 2008;Pal, 2009;Perseghin, 2010;Matschinsky et al, 2011). A broad diversity of chemical entities including benzamide derivatives (Iino et al, 2010;Pike et al, 2011;Li et al, 2011;Mao et al, 2012;Zhang et al, 2012;Park et al, 2013;Park et al, 2014;Singh et al, 2016;Tsumura et al, 2017;Wang et al, 2017;Charaya et al, 2018), acetamides (Mitsuya et al, 2009;Pfefferkorn et al, 2012;Cheruvallath et al, 2013), carboxamides (Li et al, 2010;Pfefferkorn et al, 2012a;Ye et al, 2012), acrylamides (Sidduri et al, 2010), benzimidazoles (Ishikawa et al, 2009;Takahashi et al, 2009), quinazolines (Iino et al, 2009), thiazoles (Hinklin et al, 2013), pyrimidines (Filipski et al, 2013), and urea derivatives (Zhang et al, 2012a;Li et al, 2014) have been reported in last few years to act as potent GK activators. The maximum research efforts related to GK activators had mainly focused on the benzamide derivatives owing to their orientation and binding pattern in the allosteric binding site of the GK protein (Grewal et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Antidiabetic Activity of Novel Sulfamoyl Benzamide Derivatives as Glucokinase Activators

Grewal

Sharma

Singh

et al. 2018

JPTRM

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The present work has been planned to design, synthesize and evaluate the antidiabetic potential of a series of sulfamoyl benzamide derivatives as potential glucokinase (GK) activators. A new series of sulfamoyl benzamide derivatives was synthesized starting from 3-nitrobenzoic acid and characterized. In silico docking studies were performed to determine the binding interactions for the best fit conformations in the allosteric site of GK enzyme. Based on the results of in silico studies, the selected molecules were tested for their antidiabetic activity in animal studies (alloxan induced diabetic animal model). Compound 7 exhibited highest antidiabetic activity in animal studies. The results of in vivo antidiabetic activity studies were found to be in parallel to that of docking studies. These newly synthesized sulfamoyl benzamide derivatives thus can be treated as the initial hits for the development of novel, safe, effective and orally bioavailable GK activators as therapeutic agents for the treatment of type 2 diabetes.

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Discovery of a novel phenylethyl benzamide glucokinase activator for the treatment of type 2 diabetes mellitus

Cited by 30 publications

References 18 publications

β-Caryophyllene, a natural sesquiterpene, modulates carbohydrate metabolism in streptozotocin-induced diabetic rats

β-Caryophyllene, a natural sesquiterpene, modulates carbohydrate metabolism in streptozotocin-induced diabetic rats

N‐pyridin‐2‐yl benzamide analogues as allosteric activators of glucokinase: Design, synthesis, in vitro, in silico and in vivo evaluation

Design, Synthesis and Antidiabetic Activity of Novel Sulfamoyl Benzamide Derivatives as Glucokinase Activators

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