Discovery of a Clinical Candidate from the Structurally Unique Dioxa-bicyclo[3.2.1]octane Class of Sodium-Dependent Glucose Cotransporter 2 Inhibitors

Mascitti, Vincent; Maurer, Tristan S.; Robinson, Ralph P.; Bian, Jianwei; Boustany-Kari, Carine M.; Brandt, Thomas A.; Collman, Benjamin M.; Kalgutkar, Amit S.; Klenotic, Michelle K.; Leininger, Michael T.; Lowe, André; Maguire, R. James; Masterson, Victoria M.; Miao, Zhuang; Mukaiyama, Emi; Patel, Jigna D.; Pettersen, John C.; Préville, Cathy; Samas, Brian; She, Li; Sobol, Zhanna; Steppan, Claire M.; Stevens, Benjamin D.; Thuma, Benjamin A.; Tugnait, Meera; Zeng, Dongxiang; Zhu, Tong

doi:10.1021/jm200049r

Cited by 113 publications

(89 citation statements)

References 31 publications

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“…Nevertheless, additional confidence that the PK/PD model predominantly represents SGLT2 inhibition can be derived from the concordance between the estimated unbound IC 50 and that previously reported for rSGLT2 in vitro (2.9 vs. 3 nM, respectively) (36). In addition, we have recently reported a similar in vitro-in vivo concordance of IC 50 in applying this PK/PD model to new SGLT2 inhibitor, PF-04971729 (27). It is interesting to note that the I max of dapagliflozin was estimated to be 0.32, indicating that maximum SGLT2 inhibition is associated with only a 32% reduction in glucose reabsorption.…”

Section: Discussion Preclinical Pharmacokinetics and Pharmacodynamicssupporting

confidence: 78%

“…This value is consistent with plasma glucose values reported in normal rats (29)(30)(31). The f reabs parameter was fixed to 0.996 as previously estimated and is commensurate with near complete glucose reabsorption in normal rats (27). As such, only I max and IC 50 were estimated in the modeling process.…”

Section: Methodssupporting

confidence: 77%

“…Plasma drug concentration and apparent volume of distribution in the central compartment are denoted by C p (initial condition=0) and V c,app , respectively. The dynamic cumulative UGE response to SGLT2 inhibition was modeled as a function of the inhibitor concentration, C, as previously described (27):…”

Section: Methodsmentioning

confidence: 99%

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Pharmacodynamic Model of Sodium–Glucose Transporter 2 (SGLT2) Inhibition: Implications for Quantitative Translational Pharmacology

Maurer

Ghosh

Haddish‐Berhane

et al. 2011

AAPS J

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ABSTRACT. Sodium-glucose co-transporter-2 (SGLT2) inhibitors are an emerging class of agents for use in the treatment of type 2 diabetes mellitus (T2DM). Inhibition of SGLT2 leads to improved glycemic control through increased urinary glucose excretion (UGE). In this study, a biologically based pharmacokinetic/pharmacodynamic (PK/PD) model of SGLT2 inhibitor-mediated UGE was developed. The derived model was used to characterize the acute PK/PD relationship of the SGLT2 inhibitor, dapagliflozin, in rats. The quantitative translational pharmacology of dapagliflozin was examined through both prospective simulation and direct modeling of mean literature data obtained for dapagliflozin in healthy subjects. Prospective simulations provided time courses of UGE that were of consistent shape to clinical observations, but were modestly biased toward under prediction. Direct modeling provided an improved characterization of the data and precise parameter estimates which were reasonably consistent with those predicted from preclinical data. Overall, these results indicate that the acute clinical pharmacology of SGLT2 inhibitors in healthy subjects can be reasonably well predicted from preclinical data through rational accounting of species differences in pharmacokinetics, physiology, and SGLT2 pharmacology. Because these data can be generated at the earliest stages of drug discovery, the proposed model is useful in the design and development of novel SGLT2 inhibitors. In addition, this model is expected to serve as a useful foundation for future efforts to understand and predict the effects of SGLT2 inhibition under chronic administration and in other patient populations.

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Section: Discussion Preclinical Pharmacokinetics and Pharmacodynamicssupporting

confidence: 78%

Section: Methodssupporting

confidence: 77%

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Pharmacodynamic Model of Sodium–Glucose Transporter 2 (SGLT2) Inhibition: Implications for Quantitative Translational Pharmacology

Maurer

Ghosh

Haddish‐Berhane

et al. 2011

AAPS J

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“…1) emerged as a candidate for further advancement (Mascitti et al, 2011). PF-04971729 demonstrated Ͼ2000-fold selectivity for SGLT2 inhibition (relative to SGLT1) in vitro and revealed a concentration-dependent glucosuria after oral administration to rats.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Species and Human Disposition of PF-04971729, a Selective Inhibitor of the Sodium-Dependent Glucose Cotransporter 2 and Clinical Candidate for the Treatment of Type 2 Diabetes Mellitus

Kalgutkar¹,

Tugnait²,

Zhu³

et al. 2011

Drug Metab Dispos

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128

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C]metformin by PF-04971729 also were very weak (IC 50 ‫؍‬ ϳ900 M). Single-species allometric scaling of rat pharmacokinetics of PF-04971729 was used to predict human clearance, distribution volume, and oral bioavailability. Human pharmacokinetic predictions were consistent with the potential for a low daily dose. First-in-human studies after oral administration indicated that the human pharmacokinetics/dose predictions for PF-04971729 were in the range that is likely to yield a favorable pharmacodynamic response.

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“…SGLT2 抑制剂多是糖苷类化合物, 是从天然产物根皮苷中改造而来的 [2] . 由于对 O-糖苷药效和安全性的担忧, 现在已经上市和在研的 SGLT2 抑制剂均是 C-糖苷, 如 Dapagliflozin [3] 、 Canagliflozin [4] 、 Empagliflozin [5] 、 Ertugliflozin [6] 等(图 1), Dapagliflozin 已分别在欧洲、美国批准上市.…”

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Design, Synthesis and Hypoglycemic Activity of Cyclopropane-BearingC-Glucosides as Sodium-Glucose Cotransporter 2 Inhibitors

史永恒¹,

周春梅²,

张盼龙³

et al. 2016

Chin. J. Org. Chem.

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A novel series of cyclopropane-bearing C-glucosides were designed and synthesized as sodium-glucose cotransporter 2 (SGLT2) inhibitors starting from the substituted bromobenzoic acids. The reaction condition for the construction of the cyclopropane moiety was studied, and a more economical synthetic route was established. All the synthesized compounds were characterized by 1 H NMR and HR-MS. In vivo evaluation of these compounds by rat urinary glucose excretion (UGE) test revealed that all the synthesized seven cyclopropane-bearing C-glucosides 1a～1g exhibited potent hypoglycemic activity, among which (1S)-1-deoxy-1-{4-chloro-3-[1-(4-ethoxyphenyl)cyclopropyl-1-yl]-phenyl}-D-glucopyranose (1e) was the most potent one but still exhibited lower hypoglycemic activity to dapagliflozin, demonstrating that the cyclopropane moiety can not be well tolerated in dapagliflozin molecule and the position of the Cl atom in dapagliflozin is the best among the analogues.

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Discovery of a Clinical Candidate from the Structurally Unique Dioxa-bicyclo[3.2.1]octane Class of Sodium-Dependent Glucose Cotransporter 2 Inhibitors

Cited by 113 publications

References 31 publications

Pharmacodynamic Model of Sodium–Glucose Transporter 2 (SGLT2) Inhibition: Implications for Quantitative Translational Pharmacology

Pharmacodynamic Model of Sodium–Glucose Transporter 2 (SGLT2) Inhibition: Implications for Quantitative Translational Pharmacology

Preclinical Species and Human Disposition of PF-04971729, a Selective Inhibitor of the Sodium-Dependent Glucose Cotransporter 2 and Clinical Candidate for the Treatment of Type 2 Diabetes Mellitus

Design, Synthesis and Hypoglycemic Activity of Cyclopropane-BearingC-Glucosides as Sodium-Glucose Cotransporter 2 Inhibitors

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