Exploration of O-spiroketal C-arylglucosides as novel and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors

Lv, Binhua; Xu, Bo; Yan, Feng; Peng, Kun; Xu, Ge; Du, Jiyan; Zhang, Lili; Zhang, Wenbin; Zhang, Ting; Zhu, Liangcheng; Ding, Haifeng; Sheng, Zelin; Welihinda, Ajith; Seed, Brian; Chen, Yuanwei

doi:10.1016/j.bmcl.2009.10.088

Cited by 36 publications

(19 citation statements)

References 17 publications

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“…82 Contrary to the Bristol-Myers Squibb findings, substitution of the diaryl methylene bridge was tolerated. Potency was unchanged upon replacement of the methylene bridge linking the two aryls with CF 2 6-9.…”

Section: Sglt2 Inhibitors In Developmentcontrasting

confidence: 52%

“…The Egret/Chengdu group, having been encouraged by the activity of 6-3, also synthesized 6-4 to better assess the potential of this series. 82 (In the Egret/ Chengdu assay SGLT2 EC 50 and selectivity for 17 were 6.7 nM and 132-fold rather than 1.1 nM and 1200-fold reported by Bristol-Myers and others.) This promising similarity in affinity for 6-4 and 17 prompted an extensive SAR evaluation of the distal ring.…”

Section: Sglt2 Inhibitors In Developmentmentioning

confidence: 75%

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Chapter 3. SGLT2 Inhibitors in Development

Washburn¹

2012

Drug Discovery

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Section: Sglt2 Inhibitors In Developmentcontrasting

confidence: 52%

Section: Sglt2 Inhibitors In Developmentmentioning

confidence: 75%

Chapter 3. SGLT2 Inhibitors in Development

Washburn¹

2012

Drug Discovery

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“…A set of 110 different SGLT2 inhibitors and 44 different SGLT1 inhibitors has been collected from different references [1,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. Of those compounds, 25 SGLT2 inhibitors and 23 SGLT1 inhibitors, which achieve satisfactory diversity in both structural and activity ranges, were selected as the training set for pharmacophore models, respectively.…”

Section: Selection Of Moleculesmentioning

confidence: 99%

A specific pharmacophore model of sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors

et al. 2011

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Sodium-dependent glucose co-transporter 2 (SGLT2) plays a pivotal role in maintaining glucose equilibrium in the human body, emerging as one of the most promising targets for the treatment of diabetes mellitus type 2. Pharmacophore models of SGLT2 inhibitors have been generated with a training set of 25 SGLT2 inhibitors using Discovery Studio V2.1. The best hypothesis (Hypo1(SGLT2)) contains one hydrogen bond donor, five excluded volumes, one ring aromatic and three hydrophobic features, and has a correlation coefficient of 0.955, cost difference of 68.76, RMSD of 0.85. This model was validated by test set, Fischer randomization test and decoy set methods. The specificity of Hypo1(SGLT2) was evaluated. The pharmacophore features of Hypo1(SGLT2) were different from the best pharmacophore model (Hypo1(SGLT1)) of SGLT1 inhibitors we developed. Moreover, Hypo1(SGLT2) could effectively distinguish selective inhibitors of SGLT2 from those of SGLT1. These results indicate that a highly predictive and specific pharmacophore model of SGLT2 inhibitors has been successfully obtained. Then Hypo1(SGLT2) was used as a 3D query to screen databases including NCI and Maybridge for identifying new inhibitors of SGLT2. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five. And several compounds selected from the top ranked hits have been suggested for further experimental assay studies.

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“…Among these derivatives benzylated aniline-, pyrrole-, and indole N-glucosides (Table 6, Entries 1-4, respectively) are potent orally active SGLT2 inhibitors (Washburn, 2009b). O-Spiroketal C-arylglucosides (Entries 5 and 6) which combine the character of both Oglucosides and C-glucosyl derivatives, show good inhibitory activity (Lv et al, 2009) and high selectivity (Washburn, 2009b) for SGLT2 which can be attributed, in part, to a greater conformational constraint imposed by the spiro-annelated ring system. In the quest of new candidates for SGLT2 inhibition the modification of the sugar part of the molecules is a further possibility.…”

Section: (Handlon 2005)mentioning

confidence: 99%