C-Glucosides with heteroaryl thiophene as novel sodium-dependent glucose cotransporter 2 inhibitors

Koga, Yasuo; Sakamaki, Shigeki; Hongu, Mitsuya; Kawanishi, Eiji; Sakamoto, Takabumi; Yamamoto, Yasuo; Kimata, Hirotaka; Nakayama, Keiko; Kuriyama, Chiaki; Matsushita, Yasuyuki; Ueta, Kiichiro; Tsuda-Tsukimoto, Minoru; Nomura, Sumihiro

doi:10.1016/j.bmc.2013.05.048

Cited by 26 publications

(17 citation statements)

References 17 publications

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“…TA-3404 is a derivative of canagliflozin [14] which has a several 100s fold much higher selectivity for SGLT2 over SGLT1 [13]. In agreement with the higher extracellular affinity or low intracellular inhibition of Pz in SGLT1 [15] TA-3404 also exhibits at least 100 times lower affinity than the extracellular affinity with SGLT2.…”

Section: Introductionmentioning

confidence: 62%

Identification of phlorizin binding domains in sodium-glucose cotransporter family: SGLT1 as a unique model system

Raja

Kinne

2015

Biochimie

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Section: Introductionmentioning

confidence: 62%

Identification of phlorizin binding domains in sodium-glucose cotransporter family: SGLT1 as a unique model system

Raja

Kinne

2015

Biochimie

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“…Previous studies (Koga et al. ) have shown that, in CHOK1 cells overexpressing hSGLT1 or hSGLT2, TA‐3404 is a potent, selective inhibitor for hSGLT2. TA‐3404 inhibited Na + ‐dependent 14 C‐ α ‐methylglucoside ( α ‐MDG) uptake with an IC 50 of 2 nmol/L against SGLT2 and 750 nmol/L against SGLT1 (~350‐fold selectivity for SGLT2 vs. SGLT1).…”

Section: Resultsmentioning

confidence: 95%

“…TA‐3404 is a derivative of canagliflozin (Koga et al. ) with an IC 50 for hSGLT2 of 2 nmol/L. Canagliflozin has been demonstrated to be a highly potent and selective inhibitor of hSGLT2.…”

Section: Discussionmentioning

confidence: 99%

“…) (Janssen Research & Development LLC) stock solution was prepared in DMSO at a concentration of 100 mmol/L (Koga et al. ).…”

Section: Methodsmentioning

confidence: 99%

“…In this study, we have directly tested if the specific SGLT2 inhibitor JNJ‐30980924/TA‐3404 (Koga et al. ) (Fig. ) can inhibit hSGLT2 from the cytosolic surface using a whole‐cell patch‐clamp method.…”

Section: Introductionmentioning

confidence: 99%

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SGLT2 inhibitors act from the extracellular surface of the cell membrane

et al. 2014

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SGLT2 inhibitors are a new class of drugs that have been recently developed to treat type II diabetes. They lower glucose levels by inhibiting the renal Na+/glucose cotransporter SGLT2, thereby increasing the amount of glucose excreted in the urine. Pharmacodynamics studies have raised questions about how these inhibitors reach SGLT2 in the brush border membrane of the S1 and S2 segments of the renal proximal tubule: are these drugs filtered by the glomerulus and act extracellularly, or do they enter the cell and act intracellularly? To address this question we expressed hSGLT2 in HEK‐293T cells and determined the affinity of a specific hSGLT2 inhibitor, TA‐3404 (also known as JNJ‐30980924), from the extra‐ and intracellular side of the plasma membrane. Inhibition of SGLT2 activity (Na+/glucose currents) by TA‐3404 was determined using the whole‐cell patch clamp that allows controlling the composition of both the extracellular and intracellular solutions. We compared the results to those obtained using the nonselective SGLT inhibitor phlorizin, and to the effect of TA‐3404 on hSGLT1. Our results showed that TA‐3404 is a potent extracellular inhibitor of glucose inward SGLT2 transport (IC50 2 nmol/L) but it was ineffective from the intracellular compartment at both low (5 mmol/L) and high (150 mmol/L) intracellular NaCl concentrations. We conclude that TA‐3404 only inhibits SGLT2 from the extracellular side of the plasma membrane, suggesting that it is filtered from the blood through the glomerulus and acts from within the tubule lumen.

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Thiophene derivatives: A potent multitargeted pharmacological scaffold

Singh

Bedi

2020

Journal of Heterocyclic Chem

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Despite a significant work that has been done on thiophene, continuous efforts are still being made by the researchers to identify novel heterocyclic compounds with potential bioactivities. Thiophene nucleus has been extensively utilized by the researchers across the globe for the development of diverse bioactive heterocycles for hitting a wide range of biological targets. This review throws light on synthetic approaches that have been used for the synthesis of potential thiophene derivatives followed by the depth analysis of them with respect to their pharmacological significance. This review can help the medicinal chemists and researchers to develop novel leads having thiophene nucleus with high efficacy and reduced side effects.

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C-Glucosides with heteroaryl thiophene as novel sodium-dependent glucose cotransporter 2 inhibitors

Cited by 26 publications

References 17 publications

Identification of phlorizin binding domains in sodium-glucose cotransporter family: SGLT1 as a unique model system

Identification of phlorizin binding domains in sodium-glucose cotransporter family: SGLT1 as a unique model system

SGLT2 inhibitors act from the extracellular surface of the cell membrane

Thiophene derivatives: A potent multitargeted pharmacological scaffold

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