Discovery of potent and orally active 3-alkoxy-5-phenoxy-N-thiazolyl benzamides as novel allosteric glucokinase activators

Iino, Tomoharu; Tsukahara, Daisuke; Kamata, Kenji; Sasaki, Kaori; Ohyama, Seiichi; Hosaka, Hideka; Hasegawa, Tomomi; Chiba, Masato; Nagata, Yasufumi; Eiki, Jun-ichi; Nishimura, Teruyuki

doi:10.1016/j.bmc.2009.02.038

Cited by 54 publications

(35 citation statements)

References 15 publications

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“…It is possible that, over the next 5-10 years, we will see patients with not only GCK-PNDM but also T2DM being treated by novel pharmacological agents that activate glucokinase by a similar mechanism to the mutations that result in GCK-HH. The identification of several classes of small molecule glucokinase activators (GKAs) that bind to the GCK allosteric activator site has drawn considerable recent interest [Bertram et al, 2008;Efanov et al, 2005;Grimsby et al, 2008;Iino et al, 2009;McKerrecher et al, 2006] and at least one GCK-targeted activator is undergoing Phase I clinical trials as a diabetes therapy [Grimsby et al, 2003;Guertin and Grimsby, 2006;McKerrecher et al, 2006]. A recent review has been published outlining the scientific basis and developmental progress of various GKAs [Matschinsky, 2009].…”

Section: Future Prospectsmentioning

confidence: 98%

Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia

et al. 2009

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Glucokinase is a key regulatory enzyme in the pancreatic beta-cell. It plays a crucial role in the regulation of insulin secretion and has been termed the glucose sensor in pancreatic beta-cells. Given its central role in the regulation of insulin release it is understandable that mutations in the gene encoding glucokinase (GCK) can cause both hyper- and hypoglycemia. Heterozygous inactivating mutations in GCK cause maturity-onset diabetes of the young (MODY) subtype glucokinase (GCK), characterized by mild fasting hyperglycemia, which is present at birth but often only detected later in life during screening for other purposes. Homozygous inactivating GCK mutations result in a more severe phenotype presenting at birth as permanent neonatal diabetes mellitus (PNDM). A growing number of heterozygous activating GCK mutations that cause hypoglycemia have also been reported. A total of 620 mutations in the GCK gene have been described in a total of 1,441 families. There are no common mutations, and the mutations are distributed throughout the gene. The majority of activating mutations cluster in a discrete region of the protein termed the allosteric activator site. The identification of a GCK mutation in patients with both hyper- and hypoglycemia has implications for the clinical course and clinical management of their disorder.

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Section: Future Prospectsmentioning

confidence: 98%

Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia

et al. 2009

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“…The GKA activity (EC 50 in lM) data of 3-alkoxy-5-phenoxy-N-thiazolyl benzamide analogs were taken from the reported work of Iino et al (2009) (Table 1). In attempting QSAR, these EC 50 data were converted to negative logarithmic dose in moles (pEC 50 ) because QSAR is a linear free energy relationship, and from the van't Hoff isotherm, free energy change during a process is proportional to the logarithm of the rate or equilibrium constant of the process.…”

Section: Methodsmentioning

confidence: 99%

“…The study was performed on a series of 3-alkoxy-5-phenoxy-N-thiazolyl benzamides analogs (Iino et al, 2009). The emphasis was focused on the quantification of structure activity relationship with a view to delineate the influence of key GKAs activity, which will aid in the designing of potent and safer drugs.…”

Section: Introductionmentioning

confidence: 99%

Rationalization of physicochemical characters and docking of 3-alkoxy-5-phenoxy-N-thiazolyl benzamide analogs toward glucokinase activator activity

Gupta¹,

Sabarwal²,

Patidar³

et al. 2011

Med Chem Res

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Diabetes mellitus is a chronic metabolic disorder involving the dysregulation of glucose metabolism, b-cell dysfunction, and impaired insulin sensitivity. Glucokinase (GK) promotes glycogen synthesis, while it enhances insulin secretion from pancreatic b-cells. In this study, we focused on molecular modeling study of 3-alkoxy-5-phenoxy-N-thiazolyl benzamide analogs with reference to structural requirements. The amalgamated best fit consensus scoring function showed coefficient of determination (0.927), leave-one-out cross-validated squared correlation coefficient (0.865), and external predictivity value (0.763). The binding of 3-alkoxy-5-phenoxy-Nthiazolyl benzamide analogs to glucokinase enzyme was explored with the help of docking. The most stable ligandenzyme complex of compound TR-2 showed that the NH of the benzamide make key hydrogen bonds with the backbone C=O of Arg63. The phenoxy moiety on the 5th position of benzene ring occupies the hydrophobic space on the allosteric binding site constituted from Met210, Met235, Cys220, and Tyr214. One of the oxygen of methylsulfonyl group forms hydrogen bond with NE2 of Gln98 and phenyl ring and the aromatic ring of Tyr215 are perpendicular to each other, which probably increase potency due to van der Waals interactions.The structural insights gleaned from the study could be usefully employed to design activators with a much more enhanced potency.

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“…Thiazole derivatives display a wide range of biological activities such as antimicrobial, anticancer and antidiabetic agents …”

Section: Introductionmentioning

confidence: 99%

Microwave Assisted Three Component One‐pot Synthesis of Bis(aminoazolo[1,5‐a]pyrimidines) and Bis(aminoazino[1,2‐a]benzimidazoles) Bearing Thiazole Moiety

2019

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Novel bis[(thiazol‐2‐yl)acetonitrile] derivatives were prepared in good yields by the cyclocondensation of bis(bromoacetyl) derivatives with two equivalents of 2‐cyanothioacetamide in dioxane at reflux. The bis[(thiazol‐2‐yl)acetonitrile] derivatives were taken as synthetic precursors for the synthesis of novel bis(aminoazolo[1,5‐a]pyrimidines), bearing thiazole moiety. The target molecules were prepared by the three component one pot reaction of bis[(thiazol‐2‐yl)acetonitrile] derivatives, dimethylformamide‐dimethylacetal and several of 3‐aminopyrazoles in pyridine under microwave irradiation at 140 °C for 2 h. Using the same protocol, novel bis(aminotriazolo[1,5‐a]pyrimidines), bis(aminopyrimido[1,2‐a]benzimidazoles) and bis(aminopyrido[1,2‐a]benzimidazoles), incorporating thiazole moieties, were prepared by using the appropriate heterocyclic amine or 2‐(1H‐benzoimidazol‐2‐yl)acetonitrile instead of 3‐aminopyrazoles. The structure of the newly prepared thiazoles was confirmed via considering their elemental analyses and spectral data.

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Discovery of potent and orally active 3-alkoxy-5-phenoxy-N-thiazolyl benzamides as novel allosteric glucokinase activators

Cited by 54 publications

References 15 publications

Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia

Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia

Rationalization of physicochemical characters and docking of 3-alkoxy-5-phenoxy-N-thiazolyl benzamide analogs toward glucokinase activator activity

Microwave Assisted Three Component One‐pot Synthesis of Bis(aminoazolo[1,5‐a]pyrimidines) and Bis(aminoazino[1,2‐a]benzimidazoles) Bearing Thiazole Moiety

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