Discovery and hit-to-lead optimization of novel allosteric glucokinase activators

Lang, Martin; Seifert, Markus H. J.; Wolf, Kristina K.; Aschenbrenner, Andrea; Baumgartner, Roland; Wieber, Tanja; Trentinaglia, Viola; Blisse, Marcus; Tajima, Nobumitsu; Yamashita, Tetsuo; Vitt, Daniel; Noda, Hitoshi

doi:10.1016/j.bmcl.2011.06.128

Cited by 18 publications

(7 citation statements)

References 57 publications

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“…A three-pillar approach including similarity search, structural alignment, and a conventional chemist's structural search resulted in 200 compounds and tested for GK activity. Compounds 18 and 19 were identified as potent compounds and used for further optimization (Lang et al, 2011). A privileged-fragment-merging (PFM) strategy was applied to generate a series of new benzamide derivatives (Mao et al, 2012).…”

Section: Azole Derivativesmentioning

confidence: 99%

A comprehensive review on glucokinase activators: Promising agents for the treatment of Type 2 diabetes

et al. 2021

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Glucokinase is a key enzyme which converts glucose into glucose-6-phosphate in the liver and pancreatic cells of the human. In the liver, glucokinase promotes the synthesis of glycogen, and in the pancreas, it helps in glucose-sensitive insulin release. It serves as a "glucose sensor" and thereby plays an important role in the regulation of glucose homeostasis. Due to this activity, glucokinase is considered as an attractive drug target for type 2 diabetes. It created a lot of interest among the researchers, and several small molecules were discovered. The research work was initiated in 1990. However, the hypoglycemic effect, increased liver burden, and loss of efficacy over time were faced during clinical development. Dorzagliatin, a novel glucokinase activator that acts on both the liver and pancreas, is in the latestage clinical development. TTP399, a promising hepatoselective GK activator, showed a clinically significant and sustained reduction in glycated hemoglobin with a low risk of adverse effects. The successful findings generated immense interest to continue further research in finding small molecule GK activators for the treatment of type 2 diabetes. The article covers different series of GK activators reported over the past decade and the structural insights into the GK-GK activator binding which, we believe will stimulate the discovery of novel GK activators to treat type 2 diabetes.

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Section: Azole Derivativesmentioning

confidence: 99%

A comprehensive review on glucokinase activators: Promising agents for the treatment of Type 2 diabetes

et al. 2021

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“…After the selection of lead compounds, the next step comprises the process of lead optimization (LO). At the optimization stage, structure-(SBDD) and ligand-based drug design (LBDD) methods are performed to improve the pharmacodynamics, pharmacokinetics and safety of the leads [17,18]. The understanding of such a broad range of parameters is essential to provide the right balance in the characterization of the most promising compounds for further investigation [19].…”

Section: Medicinal Chemistry and Drug Discoverymentioning

confidence: 99%

Medicinal Chemistry Approaches to Neglected Diseases Drug Discovery

Andricopulo¹,

Ferreira²

2014

J. Mod. Med. Chem.

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The prevalence of a variety of neglected diseases is an increasing serious public health problem in developing countries, particularly in the poorest and most remote areas with very little or no access to medical care. The consequences in terms of morbidity and mortality due to these infections are devastating and have a major social and economic impact in several relevant aspects. According to the World Health Organization, these diseases are one of the most important scientific and technological challenges that face humankind in the 21st century. Although they affect more than a billion people around the world, there are only a few safe and effective drugs currently available. The urgent need for new drugs has led pharmaceutical and academic R&D centers to employ more knowledge-based platforms, as an unprecedented opportunity to make a significant impact on the lives of disadvantaged people through the discovery of novel therapeutic options. In this perspective we discuss the successful application of modern medicinal chemistry approaches to neglected diseases.

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“…The present work is devoted to the synthesis and evaluation of anticancer activity [of] N-(5-R-benzyl-1,3-thiazol-2-yl)-2,5-dimethyl-3-furamides using diazonium salts as a starting material. Noteworthy, N-1,3-thiazol-2-yl furamides display biological activity of different kind such as antivarial [17] and antibacterial [18], they are effective against both replicative and latent mycobacterium tuberculosis [19,20], malaria parasites [21], as well as the ligands of adenosine receptors [22], allosteric glucokinase activators [23]and the inhibitors of the Src family kinase p56Lck [24]. The anticancer properties of N-1,3-thiazol-2-yl furamides were also reported [25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and anticancer properties of N-(5-R-benzyl-1,3-thiazol-2-yl)-2,5-dimethyl-3-furamides

et al. 2020

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Study of the synthesis and anticancer activity of a series of N-(5-R-benzyl-1,3-thiazol-2-yl)-2,5-dimethyl-3-furamides. Methods. Organic synthesis, analytical and spectral methods, pharmacological screening. Results. N-(5-R-benzyl-1,3-thiazol-2-yl)-2,5-dimethyl-3-furamides 7a-g have been prepared in good yields by the reaction of 2-amino-5-(R-benzyl)thiazoles with 2,5-dimethyl-3-furoylchloride. Their structure was confirmed by 1 H NMR spectroscopy and microanalyses. The synthesized compounds have been evaluated for their anticancer activity against 60 cancer lines in the concentration of 10 µM. The human tumour cell lines were derived from nine different cancer types: leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers. It was found that compounds 7d,e,g exhibit a high activity with GP = 29.05-35.02 % whereas 7a-c,f -moderate activity with GP = 60.31-67.36 %. The most active compound 7g showed a high inhibition activity (GI 50 <10 µM) against 54 of 58 human tumor cell lines with average GI 50 values of 4.22 µM and the colon cancer subpanel demonstrated the highest sensitivity with [a] mean GI 50 value of 2.53 µM. The most sensitive line was T-47D (BreastCancer, GI 50 = 0.088 µM). [The] MG-MID values for the most active compound 7g are less compared with those for 5-fluorouracil, curcumin and cisplatin when testing in the same manner. Conclusions. A series of new N-(5-R-benzyl-1,3-thiazol-2-yl)-2,5dimethyl-3-furamides were prepared. The compounds with high anticancer activity have been identified.

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Discovery and hit-to-lead optimization of novel allosteric glucokinase activators

Cited by 18 publications

References 57 publications

A comprehensive review on glucokinase activators: Promising agents for the treatment of Type 2 diabetes

A comprehensive review on glucokinase activators: Promising agents for the treatment of Type 2 diabetes

Medicinal Chemistry Approaches to Neglected Diseases Drug Discovery

Synthesis and anticancer properties of N-(5-R-benzyl-1,3-thiazol-2-yl)-2,5-dimethyl-3-furamides

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