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Chemical Structure| 461432-26-8 Chemical Structure| 461432-26-8

Structure of Dapagliflozin
CAS No.: 461432-26-8

Chemical Structure| 461432-26-8

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Dapagliflozin (BMS-512148), a new agent for treating diabetes mellitus (DM), is a competitive inhibitor of sodium/glucose cotransporter 2 (SGLT2), leading to glucose excretion in the urine. Dapagliflozin induces HIF1 expression and reduces renal IR injury.

Synonyms: BMS-512148

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Ahasanul Hasan ; Sreelakshmi N. Menon ; Farzana Zerin ; Raquibul Hasan ;

Abstract: Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that, in addition to glucose reduction, lowers systemic blood pressure. Here, we investigated if dapagliflozin could directly relax small mesenteric arteries that control peripheral vascular resistance and blood pressure, and the underlying molecular mechanism. We used pressurized arterial myography, pharmacological inhibition and Western blotting to investigate the direct effect of dapagliflozin on the contractility of freshly isolated, resistance-size rat mesenteric arteries. Our pressure myography data unveiled that dapagliflozin relaxed small mesenteric arteries in a concentration-dependent manner. Non-selective inhibition of KV channels and selective inhibition of smooth muscle cell voltage-gated K+ channels KV7 attenuated dapagliflozin-induced vasorelaxation. Inhibition of other major KV isoforms such as KV1.3, KV1.5 channels as well as large-conductance Ca2+-activated K+ (BKCa) channels, ATP-sensitive (KATP) channels did not abolish vasodilation. Dapagliflozin-evoked vasodilation remained unaltered by pharmacological inhibition of endothelium-derived nitric oxide (NO) signaling, prostacyclin (PGI2), as well as by endothelium denudation. Our Western blotting data revealed that SGLT2 protein is expressed in rat mesenteric arteries. However, non-selective inhibition of SGLTs did not induce vasodilation, demonstrating that the vasodilatory action is independent of SGLT2 inhibition. Overall, our data suggests that dapagliflozin directly and selectively stimulates arterial smooth muscle cells KV7 channels, leading to vasodilation in resistance-size mesenteric arteries. These findings are significant as it uncovers for the first time a direct vasodilatory action of dapagliflozin in resistance mesenteric arteries, which may lower systemic blood pressure.

Keywords: Dapagliflozin ; Vascular resistance ; Mesenteric arteries ; Vasodilation ; Voltage-gated K+ channels

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Product Details of Dapagliflozin

CAS No. :461432-26-8
Formula : C21H25ClO6
M.W : 408.87
SMILES Code : ClC(C=CC([C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1)=C2)=C2CC3=CC=C(OCC)C=C3
Synonyms :
BMS-512148
MDL No. :MFCD13182359
InChI Key :JVHXJTBJCFBINQ-ADAARDCZSA-N
Pubchem ID :9887712

Safety of Dapagliflozin

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H302-H319-H372-H411
Precautionary Statements:P260-P264-P270-P273-P280-P301+P312+P330-P305+P351+P338-P314-P337+P313-P391-P501
Class:9
UN#:3077
Packing Group:

Isoform Comparison

Biological Activity

Target
  • SGLT2

    hSGLT2, EC50:1.1 nM

Clinical Trial:

NCT Number Conditions Phases Recruitment Completion Date Locations
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NCT00831779 - Completed - -
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NCT02520518 - Terminated(Designed a new modi... More >>fied/simplified protocol see NCT 03180489) Less << - -
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NCT02719756 Diabetes Mellitus ... More >> Hypoglycemic Episodes Less << Phase 4 Unknown December 2016 Russian Federation ... More >> Research Clinical Centre of the Russian Railways, JSC Not yet recruiting Moscow, Russian Federation, 125993 Contact: Alexander Ametov, prof., MD    (499)1510951 ext 8107    alexander.ametov@gmail.ru    Contact: Viktoria Blagova, PhD cand.    (499)6130363 ext 8107    vika-blagova@mail.ru Less <<
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NCT03152084 Diabetes Mellitus, Type 2|Kidn... More >>ey Function Tests Less << PHASE4 TERMINATED 2020-03-20 Research Site, Almelo, 7609 PP... More >>, Netherlands|Research Site, Amsterdam, 1081 HV, Netherlands|Research Site, Stockholm, 14186, Sweden|Research Site, ?rebro, 70185, Sweden Less <<
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NCT02719132 Diabetes Mellitus Type 2 Phase 4 Withdrawn November 2017 -
NCT02475070 Type 2 Diabetes Phase 4 Completed - Sweden ... More >> Lund University Lund, Sweden, 22184 Less <<
NCT03331289 Diabetes Mellitus, Type 2 Phase 4 Recruiting October 30, 2019 United States, Texas ... More >> University Health System Texas Diabetic Institute Recruiting San Antonio, Texas, United States, 78207 Contact: Ralph DeFronzo, MD    210-567-6691    defronzo@uthscsa.edu Less <<
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NCT02725593 Type 2 Diabetes Phase 3 Recruiting April 24, 2020 -
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NCT02981966 Diabetes Mellitus, Type 2 Phase 4 Not yet recruiting January 2021 United States, Texas ... More >> University of Texas Health Science Center San Antonio, Texas, United States, 78229 Less <<
NCT02426541 - Completed - -
NCT02577159 Diabetes Mellitus, Type 2 PHASE4 UNKNOWN 2018-08-31 Sousei Hospital, Kadoma, Osaka... More >>, 5710025, Japan|Osaka Central Hospital, Osaka city, Osaka, 5300001, Japan|Osaka University Hospital, Suita, Osaka, 5650871, Japan Less <<
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NCT02413398 Type 2 Diabetes Mellitus Phase 3 Completed - -
NCT02413398 - Completed - -
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NCT02857764 - Completed - -
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NCT02597049 - Completed - -
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NCT03209089 - Active, not recruiting December 16, 2018 Russian Federation ... More >> Research Site Belgorod Region, Shebekino, Russian Federation, D1690R00037 Research Site Belgorod Region, Volokonovsky R-n, P. Volokonovka, Russian Federation, D1690R00037 Research Site Gis-Khrustalny, Russian Federation, D1690R00037 Research Site Izhevsk, Russian Federation, D1690R00037 Research Site Kazan, Russian Federation, D1690R00037 Research Site Lipetsk, Russian Federation, D1690R00037 Research Site N. Novgorod Region, Russian Federation, D1690R00037 Research Site N. Novgorod, Russian Federation, D1690R00037 Research Site Novomoskovsk, Russian Federation, D1690R00037 Research Site Novosibirsk, Russian Federation, D1690R00037 Research Site Perm, Russian Federation, D1690R00037 Research Site Ryazan, Russian Federation, D1690R00037 Research Site Samara, Russian Federation, D1690R00037 Research Site St-petersburg, Russian Federation, D1690R00037 Research Site Tambov Region, Russian Federation, D1690R00037 Research Site Volzhsk, Russian Federation, D1690R00037 Research Site Voronezh Region, Novovoronezh, Russian Federation, D1690R00037 Research Site Voronezh, Russian Federation, D1690R00037 Research Site Yaroslavl, Russian Federation, D1690R00037 Research Site Yoshkar-Ola, Russian Federation, D1690R00037 Less <<
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NCT03627039 - Not yet recruiting August 1, 2020 -
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Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

2.45mL

0.49mL

0.24mL

12.23mL

2.45mL

1.22mL

24.46mL

4.89mL

2.45mL

Dissolving Methods
Please choose the appropriate dissolution scheme according to your animal administration guide.For the following dissolution schemes, clear stock solution should be prepared according to in vitro experiments, and then cosolvent should be added in turn:

in order to ensure the reliability of the experimental results, the clarified stock solution can be properly preserved according to the storage conditions; The working fluid for in vivo experiment is recommended to be prepared now and used on the same day;

The percentage shown in front of the following solvent refers to the volume ratio of the solvent in the final solution; If precipitation or precipitation occurs in the preparation process, it can be assisted by heating and/or ultrasound.
Protocol 1
Protocol 2
The prepared working fluid is recommended to be prepared now and used up as soon as possible in a short period of time. The percentage shown in front of the following solvent refers to the volume ratio of the solvent in the final solution; If precipitation or precipitation occurs in the preparation process, it can be assisted by heating and/or ultrasound.
Protocol 1

References

[1]Han S, Hagan DL, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008 Jun;57(6):1723-9.

[2]Perry RJ, Rabin-Court A, et al. Dehydration and insulinopenia are necessary and sufficient for euglycemic ketoacidosis in SGLT2 inhibitor-treated rats. Nat Commun. 2019 Feb 1;10(1):548.

[3]Erdogan MA, Yusuf D, et al. Highly selective SGLT2 inhibitor dapagliflozin reduces seizure activity in pentylenetetrazol-induced murine model of epilepsy. BMC Neurol. 2018 Jun 7;18(1):81.

[4]Meng W, Ellsworth BA, et al. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem. 2008 Mar 13;51(5):1145-9.

[5]Meng W, Ellsworth BA, Nirschl AA, McCann PJ, Patel M, Girotra RN, Wu G, Sher PM, Morrison EP, Biller SA, Zahler R, Deshpande PP, Pullockaran A, Hagan DL, Morgan N, Taylor JR, Obermeier MT, Humphreys WG, Khanna A, Discenza L, Robertson JG, Wang A, Han S, Wetterau JR, Janovitz EB, Flint OP, Whaley JM, Washburn WN. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem. 2008 Mar 13;51(5):1145-9. doi: 10.1021/jm701272q. Epub 2008 Feb 9. PMID: 18260618.

[6]Han S, Hagan DL, Taylor JR, Xin L, Meng W, Biller SA, Wetterau JR, Washburn WN, Whaley JM. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008 Jun;57(6):1723-9. doi: 10.2337/db07-1472. Epub 2008 Mar 20. PMID: 18356408.

 

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