|
Inhibition of human SGLT2 expressed in CHO cells assessed as inhibition of [14C]AMG accumulation
|
Homo sapiens
|
1.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.
Year : 2008
Volume : 51
Issue : 5
First Page : 1145
Last Page : 1149
Authors : 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.
Abstract : The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.
|
Inhibition of rat SGLT2 expressed in CHO cells assessed as inhibition of [14C]AMG accumulation
|
Rattus norvegicus
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.
Year : 2008
Volume : 51
Issue : 5
First Page : 1145
Last Page : 1149
Authors : 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.
Abstract : The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.
|
Inhibition of human GLUT1-mediated 2-deoxyglucose uptake in human adipocytes at 20 uM
|
Homo sapiens
|
8.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.
Year : 2008
Volume : 51
Issue : 5
First Page : 1145
Last Page : 1149
Authors : 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.
Abstract : The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.
|
Inhibition of human GLUT4-mediated 2-deoxyglucose uptake in human adipocytes at 20 uM
|
Homo sapiens
|
8.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.
Year : 2008
Volume : 51
Issue : 5
First Page : 1145
Last Page : 1149
Authors : 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.
Abstract : The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.
|
Inhibition of human kidney SGLT2 assessed as renal glucose reabsorption
|
Homo sapiens
|
1.1
nM
|
|
Journal : J. Med. Chem.
Title : Development of the renal glucose reabsorption inhibitors: a new mechanism for the pharmacotherapy of diabetes mellitus type 2.
Year : 2009
Volume : 52
Issue : 7
First Page : 1785
Last Page : 1794
Authors : Washburn WN.
|
Inhibition of rat SGLT2
|
Rattus norvegicus
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of the renal glucose reabsorption inhibitors: a new mechanism for the pharmacotherapy of diabetes mellitus type 2.
Year : 2009
Volume : 52
Issue : 7
First Page : 1785
Last Page : 1794
Authors : Washburn WN.
|
Inhibition of human SGLT2 expressed in HEK293.ETN cells assessed as methyl-alpha-D-[U-14C]glucopyranoside uptake by scintillation counting
|
Homo sapiens
|
6.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : O-Spiro C-aryl glucosides as novel sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors.
Year : 2009
Volume : 19
Issue : 19
First Page : 5632
Last Page : 5635
Authors : Xu B, Lv B, Feng Y, Xu G, Du J, Welihinda A, Sheng Z, Seed B, Chen Y.
Abstract : Two series of O-spiro C-aryl glucosides were synthesized and tested for inhibition of hSGLT1 and hSGLT2. 6'-O-Spiro C-aryl glucosides exhibited potent in vitro hSGLT2 inhibitory activity but 2'-O-spiro C-aryl glucosides showed no in vitro hSGLT2 inhibitory activity at a screening concentration of 1microM.
|
Inhibition of human SGLT1 expressed in african green monkey COS7 cells assessed as methyl-alpha-D-[U-14C]glucopyranoside uptake by scintillation counting
|
Homo sapiens
|
885.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : O-Spiro C-aryl glucosides as novel sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors.
Year : 2009
Volume : 19
Issue : 19
First Page : 5632
Last Page : 5635
Authors : Xu B, Lv B, Feng Y, Xu G, Du J, Welihinda A, Sheng Z, Seed B, Chen Y.
Abstract : Two series of O-spiro C-aryl glucosides were synthesized and tested for inhibition of hSGLT1 and hSGLT2. 6'-O-Spiro C-aryl glucosides exhibited potent in vitro hSGLT2 inhibitory activity but 2'-O-spiro C-aryl glucosides showed no in vitro hSGLT2 inhibitory activity at a screening concentration of 1microM.
|
Inhibition of human SGLT2 expressed in HEK293.ETN cells assessed as methyl-alpha-D-[U-14C]glucopyranoside uptake at 10 nM by scintillation counting
|
Homo sapiens
|
69.7
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : O-Spiro C-aryl glucosides as novel sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors.
Year : 2009
Volume : 19
Issue : 19
First Page : 5632
Last Page : 5635
Authors : Xu B, Lv B, Feng Y, Xu G, Du J, Welihinda A, Sheng Z, Seed B, Chen Y.
Abstract : Two series of O-spiro C-aryl glucosides were synthesized and tested for inhibition of hSGLT1 and hSGLT2. 6'-O-Spiro C-aryl glucosides exhibited potent in vitro hSGLT2 inhibitory activity but 2'-O-spiro C-aryl glucosides showed no in vitro hSGLT2 inhibitory activity at a screening concentration of 1microM.
|
Inhibition of human SGLT1 expressed in african green monkey COS7 cells assessed as methyl-alpha-D-[U-14C]glucopyranoside uptake at 10 uM by scintillation counting
|
Homo sapiens
|
72.7
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : O-Spiro C-aryl glucosides as novel sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors.
Year : 2009
Volume : 19
Issue : 19
First Page : 5632
Last Page : 5635
Authors : Xu B, Lv B, Feng Y, Xu G, Du J, Welihinda A, Sheng Z, Seed B, Chen Y.
Abstract : Two series of O-spiro C-aryl glucosides were synthesized and tested for inhibition of hSGLT1 and hSGLT2. 6'-O-Spiro C-aryl glucosides exhibited potent in vitro hSGLT2 inhibitory activity but 2'-O-spiro C-aryl glucosides showed no in vitro hSGLT2 inhibitory activity at a screening concentration of 1microM.
|
Inhibition of human SGLT1 expressed in HEK293 cells assessed as inhibition of [14C]alpha-methylglucopyranoside uptake
|
Homo sapiens
|
810.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel L-xylose derivatives as selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.
Year : 2009
Volume : 52
Issue : 20
First Page : 6201
Last Page : 6204
Authors : Goodwin NC, Mabon R, Harrison BA, Shadoan MK, Almstead ZY, Xie Y, Healy J, Buhring LM, DaCosta CM, Bardenhagen J, Mseeh F, Liu Q, Nouraldeen A, Wilson AG, Kimball SD, Powell DR, Rawlins DB.
Abstract : The prevalence of diabetes throughout the world continues to increase and has become a major health issue. Recently there have been several reports of inhibitors directed toward the sodium-dependent glucose cotransporter 2 (SGLT2) as a method of maintaining glucose homeostasis in diabetic patients. Herein we report the discovery of the novel O-xyloside 7c that inhibits SGLT2 in vitro and urinary glucose reabsorption in vivo.
|
Inhibition of human SGLT2 transfected in HEK293.ETN cells assessed as AMG uptake after 1.5 hrs by scintillation counting
|
Homo sapiens
|
6.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Exploration of O-spiroketal C-arylglucosides as novel and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors.
Year : 2009
Volume : 19
Issue : 24
First Page : 6877
Last Page : 6881
Authors : Lv B, Xu B, Feng Y, Peng K, Xu G, Du J, Zhang L, Zhang W, Zhang T, Zhu L, Ding H, Sheng Z, Welihinda A, Seed B, Chen Y.
Abstract : A series of novel O-spiroketal C-arylglucosides have been prepared and evaluated in cell-based functional assays for activity against human sodium-dependent glucose co-transporters 1 and 2 (SGLT1 and 2). The core spiro[isobenzofuran-1,2'-pyran] structure proved to be an effective scaffold for diversification and a number of compounds with single digit nanomolar potency and high selectivity have been synthesized. Compound 5a promoted glucosuria when administered in vivo in rats and produced a significant blood glucose reduction effect.
|
Inhibition of human SGLT1 transfected in COS-7 cells assessed as AMG uptake after 2 hrs by scintillation counting
|
Homo sapiens
|
890.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Exploration of O-spiroketal C-arylglucosides as novel and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors.
Year : 2009
Volume : 19
Issue : 24
First Page : 6877
Last Page : 6881
Authors : Lv B, Xu B, Feng Y, Peng K, Xu G, Du J, Zhang L, Zhang W, Zhang T, Zhu L, Ding H, Sheng Z, Welihinda A, Seed B, Chen Y.
Abstract : A series of novel O-spiroketal C-arylglucosides have been prepared and evaluated in cell-based functional assays for activity against human sodium-dependent glucose co-transporters 1 and 2 (SGLT1 and 2). The core spiro[isobenzofuran-1,2'-pyran] structure proved to be an effective scaffold for diversification and a number of compounds with single digit nanomolar potency and high selectivity have been synthesized. Compound 5a promoted glucosuria when administered in vivo in rats and produced a significant blood glucose reduction effect.
|
Inhibition of human recombinant SGLT2 expressed in CHO cells by liquid scintillation counting
|
Homo sapiens
|
0.49
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: 1,3,4-Thiadiazolylmethylphenyl glucoside congeners.
Year : 2010
Volume : 18
Issue : 6
First Page : 2178
Last Page : 2194
Authors : Lee J, Lee SH, Seo HJ, Son EJ, Lee SH, Jung ME, Lee M, Han HK, Kim J, Kang J, Lee J.
Abstract : Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole moieties were designed and synthesized. Among the compounds tested, biaryl-type compounds containing pyrazine 59, 2-furan 61, and 3-thiophene 71 showed the best in vitro inhibitory activities to date (IC(50) = 3.51-7.03 nM) against SGLT2. A selected compound 61, demonstrated reasonable blood glucose-lowering effects, indicating that the information obtained from the SAR studies in this 1,3,4-thiadiazolylmethylphenyl glucoside series might help to design more active SGLT2 inhibitors that are structurally related.
|
Inhibition of human SGLT2 expressed in CHO cells assessed as inhibition of sodium-dependent methyl-alpha-D-[U-14C]glucopyranoside uptake after 2 hrs
|
Homo sapiens
|
1.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : C-Aryl glycoside inhibitors of SGLT2: Exploration of sugar modifications including C-5 spirocyclization.
Year : 2010
Volume : 20
Issue : 5
First Page : 1569
Last Page : 1572
Authors : Robinson RP, Mascitti V, Boustany-Kari CM, Carr CL, Foley PM, Kimoto E, Leininger MT, Lowe A, Klenotic MK, Macdonald JI, Maguire RJ, Masterson VM, Maurer TS, Miao Z, Patel JD, Préville C, Reese MR, She L, Steppan CM, Thuma BA, Zhu T.
Abstract : Modifications to the sugar portion of C-aryl glycoside sodium glucose transporter 2 (SGLT2) inhibitors were explored, including systematic deletion and modification of each of the glycoside hydroxyl groups. Based on results showing activity to be quite tolerant of structural change at the C-5 position, a series of novel C-5 spiro analogues was prepared. Some of these analogues exhibit low nanomolar potency versus SGLT2 and promote urinary glucose excretion (UGE) in rats. However, due to sub-optimal pharmacokinetic parameters (in particular half-life), predicted human doses did not meet criteria for further advancement.
|
Inhibition of human SGLT2 expressed in CHO cells assessed as [14C]alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counting
|
Homo sapiens
|
0.49
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: Pyridazinylmethylphenyl glucoside congeners.
Year : 2010
Volume : 20
Issue : 11
First Page : 3420
Last Page : 3425
Authors : Kim MJ, Lee J, Kang SY, Lee SH, Son EJ, Jung ME, Lee SH, Song KS, Lee M, Han HK, Kim J, Lee J.
Abstract : Novel C-aryl glucoside SGLT2 inhibitors containing pyridazine motif were designed and synthesized for biological evaluation. Among the compounds tested, pyridazine containing methylthio moiety 22l or thiadiazole ring 22ah showed the best in vitro inhibitory activities in this series (IC(50)=13.4, 11.4nM, respectively) against SGLT2 to date. Subsequently, compound 22l exhibited reasonable urinary glucose excretion and glucosuria in normal SD rats, thereby demonstrating that this pyridazine series possesses both in vitro SGLT2 inhibition and in vivo efficacy, albeit to a lower degree.
|
Inhibition of human SGLT2 expressed in HEK293 cells assessed as inhibition of [14C]alpha-methyl-D-glucopyranoside uptake after 1.5 hrs by liquid scintillation counting
|
Homo sapiens
|
6.7
nM
|
|
Journal : Bioorg. Med. Chem.
Title : ortho-Substituted C-aryl glucosides as highly potent and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors.
Year : 2010
Volume : 18
Issue : 12
First Page : 4422
Last Page : 4432
Authors : Xu B, Feng Y, Lv B, Xu G, Zhang L, Du J, Peng K, Xu M, Dong J, Zhang W, Zhang T, Zhu L, Ding H, Sheng Z, Welihinda A, Seed B, Chen Y.
Abstract : A series of 2-substituted C-aryl glucosides have been synthesized and evaluated for inhibition of hSGLT1 and hSGLT2. Introduction of an appropriate ortho substituent at the proximal phenyl ring adjacent to the glycosidic bond was found to improve SGLT2 inhibitory activity and dramatically increase selectivity for hSGLT2 over hSGLT1. Selected compounds were investigated for in vivo efficacy.
|
Inhibition of human SGLT1 expressed in african green monkey COS7 cells assessed as inhibition of [14C]alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counting
|
Homo sapiens
|
890.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : ortho-Substituted C-aryl glucosides as highly potent and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors.
Year : 2010
Volume : 18
Issue : 12
First Page : 4422
Last Page : 4432
Authors : Xu B, Feng Y, Lv B, Xu G, Zhang L, Du J, Peng K, Xu M, Dong J, Zhang W, Zhang T, Zhu L, Ding H, Sheng Z, Welihinda A, Seed B, Chen Y.
Abstract : A series of 2-substituted C-aryl glucosides have been synthesized and evaluated for inhibition of hSGLT1 and hSGLT2. Introduction of an appropriate ortho substituent at the proximal phenyl ring adjacent to the glycosidic bond was found to improve SGLT2 inhibitory activity and dramatically increase selectivity for hSGLT2 over hSGLT1. Selected compounds were investigated for in vivo efficacy.
|
Inhibition of human SGLT2
|
Homo sapiens
|
0.49
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of pyridazine and thiazole analogs as SGLT2 inhibitors.
Year : 2010
Volume : 18
Issue : 16
First Page : 6069
Last Page : 6079
Authors : Kang SY, Song KS, Lee J, Lee SH, Lee J.
Abstract : With anticipation of the improvement in biological aspects in our SGLT2 program, novel pyridazinyl and thiazolyl analogs were designed and efficiently synthesized. The installation of the pyridazine ring at the anomeric carbon of d-glucopyranose was carried out in a stereoselective fashion. On the other hand, a series of thiazolyl analogs was also synthesized through a coupling reaction between perbenzyl gluconolactone 9 and 2-lithiothiazole. Biological activities of the compounds thus prepared were evaluated by the in vitro SGLT2 inhibition assay. Considering assay results, the novel benzylpyridazinyl and benzylthiazolyl analogs, disclosed in this article, could be a quick reference to prospective SGLT2 inhibitors useful for pharmacotherapy.
|
Inhibition of human SGLT2 assessed as inhibition of methyl-alpha-D-glucopyranoside uptake by cell based assay
|
Homo sapiens
|
0.49
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrimidinylmethylphenyl glucoside as novel C-aryl glucoside SGLT2 inhibitors.
Year : 2010
Volume : 20
Issue : 23
First Page : 7046
Last Page : 7049
Authors : Lee J, Kim JY, Choi J, Lee SH, Kim J, Lee J.
Abstract : Novel C-aryl glucoside SGLT2 inhibitors containing pyrimidine motif were designed and synthesized for biological evaluation. Among the compounds assayed, pyrimidine containing methylthio moiety 11 g demonstrated the best in vitro inhibitory activity against SGLT2 in this series to date (IC(50)=10.7 nM).
|
Inhibition of human SGLT2 expressed in CHO cells assessed as inhibition of [14C]alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counting
|
Homo sapiens
|
0.49
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Exploration of SAR regarding glucose moiety in novel C-aryl glucoside inhibitors of SGLT2.
Year : 2011
Volume : 21
Issue : 2
First Page : 742
Last Page : 746
Authors : Park EJ, Kong Y, Lee JS, Lee SH, Lee J.
Abstract : In order to investigate SAR regarding glucose moiety in novel C-aryl glucoside SGLT2 inhibitors containing a thiazole motif, a series of chemical modifications on glucose was conducted to explore potential utility as a suitable replacement of glucose per se. Among the compounds prepared, deshydroxy 29 (IC(50)=7.01nM) demonstrated the best in vitro inhibitory activity against SGLT2 in this series to date. But, none of the compounds were better than the parent molecule 5 (IC(50)=1.75nM).
|
Inhibition of human SGLT2 expressed in CHO cells assessed as sodium-dependent [14C]-alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counting
|
Homo sapiens
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel N-β-D-xylosylindole derivatives as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the management of hyperglycemia in diabetes.
Year : 2011
Volume : 54
Issue : 1
First Page : 166
Last Page : 178
Authors : Yao CH, Song JS, Chen CT, Yeh TK, Hung MS, Chang CC, Liu YW, Yuan MC, Hsieh CJ, Huang CY, Wang MH, Chiu CH, Hsieh TC, Wu SH, Hsiao WC, Chu KF, Tsai CH, Chao YS, Lee JC.
Abstract : A novel series of N-linked β-D-xylosides were synthesized and evaluated for inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) in a cell-based assay. Of these, the 4-chloro-3-(4-cyclopropylbenzyl)-1-(β-D-xylopyranosyl)-1H-indole 19m was found to be the most potent inhibitor, with an EC(50) value similar to that of the natural SGLT2 inhibitor phlorizin. Further studies in Sprague-Dawley (SD) rats indicated that 19m significantly increased urine glucose excretion in a dose-dependent manner with oral administration. The antihyperglycemic effect of 19m was also observed in streptozotocin (STZ) induced diabetic SD rats. These results described here are a good starting point for further investigations into N-glycoside SGLT2 inhibitors.
|
Inhibition of human SGLT1 expressed in CHO cells assessed as sodium-dependent [14C]-alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counting
|
Homo sapiens
|
428.5
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel N-β-D-xylosylindole derivatives as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the management of hyperglycemia in diabetes.
Year : 2011
Volume : 54
Issue : 1
First Page : 166
Last Page : 178
Authors : Yao CH, Song JS, Chen CT, Yeh TK, Hung MS, Chang CC, Liu YW, Yuan MC, Hsieh CJ, Huang CY, Wang MH, Chiu CH, Hsieh TC, Wu SH, Hsiao WC, Chu KF, Tsai CH, Chao YS, Lee JC.
Abstract : A novel series of N-linked β-D-xylosides were synthesized and evaluated for inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) in a cell-based assay. Of these, the 4-chloro-3-(4-cyclopropylbenzyl)-1-(β-D-xylopyranosyl)-1H-indole 19m was found to be the most potent inhibitor, with an EC(50) value similar to that of the natural SGLT2 inhibitor phlorizin. Further studies in Sprague-Dawley (SD) rats indicated that 19m significantly increased urine glucose excretion in a dose-dependent manner with oral administration. The antihyperglycemic effect of 19m was also observed in streptozotocin (STZ) induced diabetic SD rats. These results described here are a good starting point for further investigations into N-glycoside SGLT2 inhibitors.
|
Inhibition of human SGLT2 expressed in CHO cells assessed as [14C]-alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counting
|
Homo sapiens
|
0.49
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Synthesis and SAR of Thiazolylmethylphenyl Glucoside as Novel C-Aryl Glucoside SGLT2 Inhibitors.
Year : 2011
Volume : 2
Issue : 2
First Page : 182
Last Page : 187
Authors : Song KS, Lee SH, Kim MJ, Seo HJ, Lee J, Lee SH, Jung ME, Son EJ, Lee M, Kim J, Lee J.
Abstract : Novel C-aryl glucoside SGLT2 inhibitors containing the thiazole motif were designed and synthesized for biological evaluation. Among the compounds assayed, thiazole containing furanyl moiety 14v and thiophenyl moiety 14y demonstrated the best in vitro inhibitory activity against SGLT2 in this series to date (IC50 = 0.720 nM for 14v and IC50 = 0.772 nM for 14y). Both of these compounds have been further evaluated on a urinary glucose excretion test and the urine volumes excreted.
|
Inhibition of human SGLT2 expressed in CHO cells assessed as inhibition of [14C]-alpha-methyl-D-glucopyranoside transport after 60 mins by scintillation counting
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of non-glucoside SGLT2 inhibitors.
Year : 2011
Volume : 21
Issue : 8
First Page : 2472
Last Page : 2475
Authors : Li AR, Zhang J, Greenberg J, Lee T, Liu J.
Abstract : A series of benzothiazinone and benzooxazinone derivatives were discovered as SGLT2 inhibitors. The optimization led to the discovery of compounds 31 and 32, which exhibited similar potency and better SGLT1 selectivity compared to dapagliflozin. These compounds may provide novel promising scaffolds, which are different from phlorizin-based SGLT2 inhibitors.
|
Inhibition of human SGLT1 expressed in CHO cells assessed as inhibition of [14C]-alpha-methyl-D-glucopyranoside transport after 60 mins by scintillation counting
|
Homo sapiens
|
370.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of non-glucoside SGLT2 inhibitors.
Year : 2011
Volume : 21
Issue : 8
First Page : 2472
Last Page : 2475
Authors : Li AR, Zhang J, Greenberg J, Lee T, Liu J.
Abstract : A series of benzothiazinone and benzooxazinone derivatives were discovered as SGLT2 inhibitors. The optimization led to the discovery of compounds 31 and 32, which exhibited similar potency and better SGLT1 selectivity compared to dapagliflozin. These compounds may provide novel promising scaffolds, which are different from phlorizin-based SGLT2 inhibitors.
|
Inhibition of SGLT6 expressed in CHO cells assessed as inhibition of [14C]-alpha-methyl-D-glucopyranoside transport after 60 mins by scintillation counting
|
None
|
380.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of non-glucoside SGLT2 inhibitors.
Year : 2011
Volume : 21
Issue : 8
First Page : 2472
Last Page : 2475
Authors : Li AR, Zhang J, Greenberg J, Lee T, Liu J.
Abstract : A series of benzothiazinone and benzooxazinone derivatives were discovered as SGLT2 inhibitors. The optimization led to the discovery of compounds 31 and 32, which exhibited similar potency and better SGLT1 selectivity compared to dapagliflozin. These compounds may provide novel promising scaffolds, which are different from phlorizin-based SGLT2 inhibitors.
|
Inhibition of human SGLT2 expressed in CHO cells assessed as inhibition of [14C]-alpha-methyl-D-glucopyranoside transport after 60 mins by scintillation counting in presence of 100% plasma
|
Homo sapiens
|
22.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of non-glucoside SGLT2 inhibitors.
Year : 2011
Volume : 21
Issue : 8
First Page : 2472
Last Page : 2475
Authors : Li AR, Zhang J, Greenberg J, Lee T, Liu J.
Abstract : A series of benzothiazinone and benzooxazinone derivatives were discovered as SGLT2 inhibitors. The optimization led to the discovery of compounds 31 and 32, which exhibited similar potency and better SGLT1 selectivity compared to dapagliflozin. These compounds may provide novel promising scaffolds, which are different from phlorizin-based SGLT2 inhibitors.
|
Inhibition of human SGLT2 expressed in CHO cells assessed as inhibition of [14C]-Glucose uptake using [14C]-methyl glucopyranoside after 60 mins by microbeta plate counting
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of triazoles as novel and potent nonphlorizin SGLT2 inhibitors.
Year : 2011
Volume : 21
Issue : 12
First Page : 3774
Last Page : 3779
Authors : Du X, Lizarzaburu M, Turcotte S, Lee T, Greenberg J, Shan B, Fan P, Ling Y, Medina JC, Houze J.
Abstract : Previous efforts have led to the identification of a potent, selective, and nonphlorizin based SGLT2 inhibitor 1. This Letter describes efforts to further optimize the potency, microsomal stability, solubility and pharmacokinetic properties of this series of SGLT2 inhibitors. From these efforts, compounds 28 and 32 have improved solubility and pharmacokinetic properties compared to compound 1.
|
Inhibition of human SGLT2 expressed in CHO cells using methyl-alpha-D-glucopyranoside by liquid scintillation counting
|
Homo sapiens
|
1.35
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Glucosides with cyclic diarylpolynoid as novel C-aryl glucoside SGLT2 inhibitors.
Year : 2011
Volume : 21
Issue : 12
First Page : 3759
Last Page : 3763
Authors : Kang SY, Kim MJ, Lee JS, Lee J.
Abstract : Novel C-aryl glucoside SGLT2 inhibitors containing cyclic diarylpolynoid motif were designed and synthesized for biological evaluation. Alkylzinc bromides have been efficiently prepared by the direct insertion of zinc metal into alkyl bromides. The organozinc reagents underwent smooth Pd-catalyzed cross-coupling reactions. Subsequent ring closing metathesis using 2nd generation Grubbs catalyst successfully generated novel class of ansa-compounds. These glucosides with cyclic diarylpolynoids demonstrated moderate in vitro inhibitory activity against SGLT2 in this series to date (IC(50)=59.5-103 nM).
|
Inhibition of human SGLT2 expressed in CHO cells assessed as [14C]-alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counter
|
Homo sapiens
|
0.49
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Thiazolylmethyl ortho-substituted phenyl glucoside library as novel C-aryl glucoside SGLT2 inhibitors.
Year : 2011
Volume : 46
Issue : 7
First Page : 2662
Last Page : 2675
Authors : Lee SH, Kim MJ, Lee SH, Kim J, Park HJ, Lee J.
Abstract : In order to investigate SAR regarding proximal phenyl ring in novel C-aryl glucoside SGLT2 inhibitors containing a thiazole motif, a series of chemical modifications on proximal phenyl ring was conducted. During a series of lead optimization efforts, ortho-allyloxyphenyl 10p or ortho-hydroxyphenyl 11a showed subnanomolar inhibitory activity against hSGLT2.
|
Inhibition of human SGLT2 expressed in african green monkey COS7 cells assessed as inhibition of [14C]-methyl-alpha-D-glucopyranoside uptake after 2 hrs by scintillation counting in presence of 25 % human plasma
|
Homo sapiens
|
3.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : C-aryl glucosides substituted at the 4'-position as potent and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.
Year : 2011
Volume : 21
Issue : 15
First Page : 4465
Last Page : 4470
Authors : Xu B, Feng Y, Cheng H, Song Y, Lv B, Wu Y, Wang C, Li S, Xu M, Du J, Peng K, Dong J, Zhang W, Zhang T, Zhu L, Ding H, Sheng Z, Welihinda A, Roberge JY, Seed B, Chen Y.
Abstract : A series of C-aryl glucosides with various substituents at the 4'-position of the distal aryl ring have been synthesized and evaluated for inhibition of hSGLT1 and hSGLT2. Introduction of alkyl or alkoxy substituents at the 4'-position was found to improve SGLT2 potency, whereas introduction of a hydrophilic group at this position was deleterious. Compounds with alkoxy-, cycloalkoxy- or cycloalkenyloxy-ethoxy scaffolds exhibited good inhibitory activity and high selectivity toward SGLT2. Selected compounds were investigated for in vivo efficacy.
|
Inhibition of human SGLT2 expressed in CHO cells assessed as reduction of [14C]-labeled AMG after 2 hrs by liquid scintillation counting
|
Homo sapiens
|
1.35
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel macrocyclic C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents.
Year : 2011
Volume : 19
Issue : 18
First Page : 5468
Last Page : 5479
Authors : Kim MJ, Lee SH, Park SO, Kang H, Lee JS, Lee KN, Jung ME, Kim J, Lee J.
Abstract : Novel macrocyclic C-aryl glucoside SGLT2 inhibitors were designed and synthesized. Two different synthetic routes of macrocyclization were adopted to prepare novel ansa SGLT2 inhibitors. Among the compounds tested, [1,7]dioxacyclopentadecine macrocycles possessing methylthiophenyl at the distal ring 40 or ethoxyphenyl at the distal ring 23 showed the best in vitro inhibitory activity in this series to date (40, IC(50)=0.778 nM and 23, IC(50)=0.899 nM) against hSGLT2.
|
Inhibition of human SGLT2 expressed in CHO cells assessed as [14C]-alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counting
|
Homo sapiens
|
0.49
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel thiophenyl C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents.
Year : 2011
Volume : 19
Issue : 19
First Page : 5813
Last Page : 5832
Authors : Lee SH, Song KS, Kim JY, Kang M, Lee JS, Cho SH, Park HJ, Kim J, Lee J.
Abstract : Novel thiophene C-aryl glucoside SGLT2 inhibitors were designed and synthesized. Two different types of thiophene derivatives were readily prepared. Among the compounds tested, ethylphenyl at the distal ring 71p showed the best in vitro inhibitory activity in this series to date (IC(50)=4.47 nM) against SGLT2.
|
Inhibition of human SGLT2 expressed in CHO-K1 cells by [14C]AMG uptake assay
|
Homo sapiens
|
1.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : C-Aryl 5a-carba-β-d-glucopyranosides as novel sodium glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.
Year : 2012
Volume : 20
Issue : 13
First Page : 4117
Last Page : 4127
Authors : Ohtake Y, Sato T, Matsuoka H, Kobayashi T, Nishimoto M, Taka N, Takano K, Yamamoto K, Ohmori M, Higuchi T, Murakata M, Morikawa K, Shimma N, Suzuki M, Hagita H, Ozawa K, Yamaguchi K, Kato M, Ikeda S.
Abstract : C-Aryl 5a-carba-β-d-glucopyranose derivatives were synthesized and evaluated for inhibition activity against hSGLT1 and hSGLT2. Modifications to the substituents on the two benzene rings resulted in enhanced hSGLT2 inhibition activity and extremely high hSGLT2 selectivity versus SGLT1. Using the created superimposed model, the reason for the high hSGLT2 selectivity was speculated to be that additional substituents occupied a new space, in a different way than known inhibitors. Among the tested compounds, the ethoxy compound 5h with high hSGLT2 selectivity exhibited more potent and longer hypoglycemic action in db/db mice than our O-carbasugar compound (1) and sergliflozin (2), which could be explained by its improved PK profiles relative to those of the two compounds. These results indicated that 5h might be a promising drug candidate for the treatment of type 2 diabetes.
|
Inhibition of human SGLT1 expressed in CHO-K1 cells by [14C]AMG uptake assay
|
Homo sapiens
|
800.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : C-Aryl 5a-carba-β-d-glucopyranosides as novel sodium glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.
Year : 2012
Volume : 20
Issue : 13
First Page : 4117
Last Page : 4127
Authors : Ohtake Y, Sato T, Matsuoka H, Kobayashi T, Nishimoto M, Taka N, Takano K, Yamamoto K, Ohmori M, Higuchi T, Murakata M, Morikawa K, Shimma N, Suzuki M, Hagita H, Ozawa K, Yamaguchi K, Kato M, Ikeda S.
Abstract : C-Aryl 5a-carba-β-d-glucopyranose derivatives were synthesized and evaluated for inhibition activity against hSGLT1 and hSGLT2. Modifications to the substituents on the two benzene rings resulted in enhanced hSGLT2 inhibition activity and extremely high hSGLT2 selectivity versus SGLT1. Using the created superimposed model, the reason for the high hSGLT2 selectivity was speculated to be that additional substituents occupied a new space, in a different way than known inhibitors. Among the tested compounds, the ethoxy compound 5h with high hSGLT2 selectivity exhibited more potent and longer hypoglycemic action in db/db mice than our O-carbasugar compound (1) and sergliflozin (2), which could be explained by its improved PK profiles relative to those of the two compounds. These results indicated that 5h might be a promising drug candidate for the treatment of type 2 diabetes.
|
Inhibition of human SGLT2 expressed in CHO-K1 cells incubated for 120 mins at 37 degC by [14C]-AMG uptake assay
|
Homo sapiens
|
2.4
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of novel C-indolylxylosides as sodium-dependent glucose co-transporter 2 inhibitors.
Year : 2012
Volume : 55
First Page : 32
Last Page : 38
Authors : Yao CH, Song JS, Chen CT, Yeh TK, Hsieh TC, Wu SH, Huang CY, Huang YL, Wang MH, Liu YW, Tsai CH, Kumar CR, Lee JC.
Abstract : Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors are the current focus on the indication for the management of hyperglycemia in diabetes. Here, a novel series of C-linked indolylxyloside-based inhibitors of SGLT2 has been discovered. Structure-activity relationship studies revealed that substituents at the 7-position of the indole moiety and a p-cyclopropylphenyl group in the distal position were necessary for optimum inhibitory activity. The pharmacokinetic study demonstrates that the most potent compound 1i is metabolically stable with a low clearance in rats. In further efficacy study, 1i is found to significantly lower blood glucose levels of streptozotocin (STZ)-induced diabetic rats.
|
Inhibition of human SGLT1 expressed in CHO-K1 cells incubated for 120 mins at 37 degC by [14C]-AMG uptake assay
|
Homo sapiens
|
593.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of novel C-indolylxylosides as sodium-dependent glucose co-transporter 2 inhibitors.
Year : 2012
Volume : 55
First Page : 32
Last Page : 38
Authors : Yao CH, Song JS, Chen CT, Yeh TK, Hsieh TC, Wu SH, Huang CY, Huang YL, Wang MH, Liu YW, Tsai CH, Kumar CR, Lee JC.
Abstract : Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors are the current focus on the indication for the management of hyperglycemia in diabetes. Here, a novel series of C-linked indolylxyloside-based inhibitors of SGLT2 has been discovered. Structure-activity relationship studies revealed that substituents at the 7-position of the indole moiety and a p-cyclopropylphenyl group in the distal position were necessary for optimum inhibitory activity. The pharmacokinetic study demonstrates that the most potent compound 1i is metabolically stable with a low clearance in rats. In further efficacy study, 1i is found to significantly lower blood glucose levels of streptozotocin (STZ)-induced diabetic rats.
|
Inhibition of human SGLT1 expressed in CHO cells assessed as inhibition of sodium-dependent [14C]methyl-alpha-D-glucopyranoside uptake after 45 mins
|
Homo sapiens
|
800.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of tofogliflozin, a novel C-arylglucoside with an O-spiroketal ring system, as a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.
Year : 2012
Volume : 55
Issue : 17
First Page : 7828
Last Page : 7840
Authors : Ohtake Y, Sato T, Kobayashi T, Nishimoto M, Taka N, Takano K, Yamamoto K, Ohmori M, Yamaguchi M, Takami K, Yeu SY, Ahn KH, Matsuoka H, Morikawa K, Suzuki M, Hagita H, Ozawa K, Yamaguchi K, Kato M, Ikeda S.
Abstract : Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.
|
Inhibition of human SGLT2 expressed in CHO cells assessed as inhibition of sodium-dependent [14C]methyl-alpha-D-glucopyranoside uptake after 45 mins
|
Homo sapiens
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of tofogliflozin, a novel C-arylglucoside with an O-spiroketal ring system, as a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.
Year : 2012
Volume : 55
Issue : 17
First Page : 7828
Last Page : 7840
Authors : Ohtake Y, Sato T, Kobayashi T, Nishimoto M, Taka N, Takano K, Yamamoto K, Ohmori M, Yamaguchi M, Takami K, Yeu SY, Ahn KH, Matsuoka H, Morikawa K, Suzuki M, Hagita H, Ozawa K, Yamaguchi K, Kato M, Ikeda S.
Abstract : Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.
|
Inhibition of human SGLT2
|
Homo sapiens
|
1.16
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of novel l-rhamnose derived acyclic C-nucleosides with substituted 1,2,3-triazole core as potent sodium-glucose co-transporter (SGLT) inhibitors.
Year : 2014
Volume : 24
Issue : 6
First Page : 1528
Last Page : 1531
Authors : Putapatri SR, Kanwal A, Banerjee SK, Kantevari S.
Abstract : Sodium-glucose co-transporter (SGLT) inhibitors are a novel class of therapeutic agents for the treatment of type 2 diabetes by preventing renal glucose reabsorption. In our efforts to identify novel inhibitors of SGLT, we synthesized a series of l-rhamnose derived acyclic C-nucleosides with 1,2,3-triazole core. The key β-ketoester building block 4 prepared from l-rhamnose in five steps, was reacted with various aryl azides to produce the respective 1,2,3-triazole derivatives in excellent yields. Deprotection of acetonide group gave the desired acyclic C-nucleosides 7a-o. All the new compounds were screened for their sodium-glucose co-transporters (SGLT1 and SGLT2) inhibition activity using recently developed cell-based nonradioactive fluorescence glucose uptake assay. Among them, 7m with IC50: 125.9nM emerged as the most potent SGLT2 inhibitor. On the other hand compound 7d exhibited best selectivity for inhibition of SGLT2 (IC50: 149.1nM) over SGLT1 (IC50: 693.2nM). The results presented here demonstrated the utility of acyclic C-nucleosides as novel SGLT inhibitors for future investigations.
|
Inhibition of full length human SGLT2 assessed as methyl-alpha-D-[U-14C]glucopyranoside uptake after 1.5 hrs by cell-based topcount scintillation counting analysis
|
Homo sapiens
|
3.2
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of deuterated C-aryl glycoside as a potent and long-acting renal sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes.
Year : 2014
Volume : 57
Issue : 4
First Page : 1236
Last Page : 1251
Authors : Xu G, Lv B, Roberge JY, Xu B, Du J, Dong J, Chen Y, Peng K, Zhang L, Tang X, Feng Y, Xu M, Fu W, Zhang W, Zhu L, Deng Z, Sheng Z, Welihinda A, Sun X.
Abstract : SGLT2 inhibitors deuterated at sites susceptible to oxidative metabolism were found to have a slightly longer tmax and half-life (t1/2), dose-dependent increase in urinary glucose excretion (UGE) in rats, and slightly superior effects on UGE in dogs while retaining similar in vitro inhibitory activities against hSGLT2. In particular, deuterated compound 41 has the potential to be a robust long-acting antidiabetic agent.
|
Inhibition of human SGLT2 expressed in CHOK1 cells assessed as inhibition of [14C]-AMG uptake after 3 hrs by microbeta scintillation counting analysis
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The design and synthesis of novel SGLT2 inhibitors: C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties.
Year : 2014
Volume : 22
Issue : 13
First Page : 3414
Last Page : 3422
Authors : Guo C, Hu M, DeOrazio RJ, Usyatinsky A, Fitzpatrick K, Zhang Z, Maeng JH, Kitchen DB, Tom S, Luche M, Khmelnitsky Y, Mhyre AJ, Guzzo PR, Liu S.
Abstract : The sodium glucose co-transporter 2 (SGLT2) has received considerable attention in recent years as a target for the treatment of type 2 diabetes mellitus. This report describes the design, synthesis and structure-activity relationship (SAR) of C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties as novel SGLT2 inhibitors. Compounds 5p and 33b demonstrated high potency in inhibiting SGLT2 and high selectivity against SGLT1. The in vitro ADMET properties of these compounds will also be discussed.
|
Inhibition of human SGLT1 expressed in CHOK1 cells assessed as inhibition of [14C]-AMG uptake after 3 hrs by microbeta scintillation counting analysis
|
Homo sapiens
|
891.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The design and synthesis of novel SGLT2 inhibitors: C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties.
Year : 2014
Volume : 22
Issue : 13
First Page : 3414
Last Page : 3422
Authors : Guo C, Hu M, DeOrazio RJ, Usyatinsky A, Fitzpatrick K, Zhang Z, Maeng JH, Kitchen DB, Tom S, Luche M, Khmelnitsky Y, Mhyre AJ, Guzzo PR, Liu S.
Abstract : The sodium glucose co-transporter 2 (SGLT2) has received considerable attention in recent years as a target for the treatment of type 2 diabetes mellitus. This report describes the design, synthesis and structure-activity relationship (SAR) of C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties as novel SGLT2 inhibitors. Compounds 5p and 33b demonstrated high potency in inhibiting SGLT2 and high selectivity against SGLT1. The in vitro ADMET properties of these compounds will also be discussed.
|
Competitive inhibition of full-length human SGLT2 expressed in CHO cells assessed as inhibition of sodium-dependent [14C]-alpha-methyl-D-glucopyranoside uptake after 2 hrs by scintillation counting
|
Homo sapiens
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Transporter-mediated tissue targeting of therapeutic molecules in drug discovery.
Year : 2015
Volume : 25
Issue : 5
First Page : 993
Last Page : 997
Authors : Zhou J, Xu J, Huang Z, Wang M.
Abstract : Tissue concentrations of endogenous chemicals and nutrients are in large part regulated by membrane transporters through their substrate specificity and differential tissue distributions. These transporters also play a key role in the disposition of therapeutic agents thus affecting their efficacy and safety profile. A transporter-mediated tissue targeting strategy, where the structural features recognized by the transporters are incorporated into the therapeutic molecule, is emerging as an effective approach in drug discovery. In this digest, we review this phenomenon and highlight recent cases in the design of liver and kidney targeted drug molecules.
|
Uptake Assay: A cDNA clone expressing human SGLT1/SGLT2 was bought from GenerScript. Having the sequence information, it was built into pcDNA5 carrier by using traditional molecular biology methods, and then the expression plasmids were transfected into Flp-in CHO cells by using Lipofetamin 200 liposomal transfection method. The transfected cells were screened for hygromycin resistance, and the single-cell clone was screened out through the process of gradient dilution. Having obtained the single-cell clone, the uptake assay of 14C-AMG in FLP-in CHO cells stably expressing SGLT1/SGLT2 was evaluated.Cells were seeded at a density of 3x104 cells per well, uptake assay was carried out after adherent cells were cultured overnight. At least 12 hours later of culture, cells were washed once by 150 microliters per well of the absorption solution KRH-NMG (120 mM NMG, 4.7 mM KCl, 1.2 mM MgCl2, 2.2 mM CaCl2, 10 mM HEPES, pH 7.4 with HCl). To every well that was cleaned with buffer KRH-Na+ and KRH-NMG.
|
Homo sapiens
|
3.0
nM
|
|
Title : Aryl glycoside compound, preparation method and use thereof
Year : 2015
|
Uptake Assay: A cDNA clone expressing human SGLT1/SGLT2 was bought from GenerScript. Having the sequence information, it was built into pcDNA5 carrier by using traditional molecular biology methods, and then the expression plasmids were transfected into Flp-in CHO cells by using Lipofetamin 200 liposomal transfection method. The transfected cells were screened for hygromycin resistance, and the single-cell clone was screened out through the process of gradient dilution. Having obtained the single-cell clone, the uptake assay of 14C-AMG in FLP-in CHO cells stably expressing SGLT1/SGLT2 was evaluated.Cells were seeded at a density of 3x104 cells per well, uptake assay was carried out after adherent cells were cultured overnight. At least 12 hours later of culture, cells were washed once by 150 microliters per well of the absorption solution KRH-NMG (120 mM NMG, 4.7 mM KCl, 1.2 mM MgCl2, 2.2 mM CaCl2, 10 mM HEPES, pH 7.4 with HCl). To every well that was cleaned with buffer KRH-Na+ and KRH-NMG.
|
Homo sapiens
|
803.0
nM
|
|
Title : Aryl glycoside compound, preparation method and use thereof
Year : 2015
|
Inhibition of human SGLT2 expressed in CHO cells assessed as reduction in [14C]AMG uptake at 10 uM after 1 hr by liquid scintillation counting method relative to control
|
Homo sapiens
|
85.4
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of novel tetrahydroisoquinoline-C-aryl glucosides as SGLT2 inhibitors for the treatment of type 2 diabetes.
Year : 2016
Volume : 114
First Page : 89
Last Page : 100
Authors : Pan X, Huan Y, Shen Z, Liu Z.
Abstract : A series of novel tetrahydroisoquinoline-C-aryl glucosides has been synthesized and evaluated for the inhibition of human SGLT2. Compared with dapagliflozin, compound 13h exhibited equivalent in vitro inhibitory activity against SGLT2, which might become a promising candidate for the treatment of type 2 diabetes.
|
Inhibition of human SGLT2 expressed in HEK293 cells assessed as reduction in 2-deoxyglucose uptake pretreated for 10 mins followed by 2-deoxyglucose addition in presence of sodium buffer measured after 1 hr by resazurin dye based fluorescence assay
|
Homo sapiens
|
0.8
nM
|
|
Journal : J Med Chem
Title : Targeting Type 2 Diabetes with C-Glucosyl Dihydrochalcones as Selective Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: Synthesis and Biological Evaluation.
Year : 2017
Volume : 60
Issue : 2
First Page : 568
Last Page : 579
Authors : Jesus AR, Vila-Viçosa D, Machuqueiro M, Marques AP, Dore TM, Rauter AP.
Abstract : Inhibiting glucose reabsorption by sodium glucose co-transporter proteins (SGLTs) in the kidneys is a relatively new strategy for treating type 2 diabetes. Selective inhibition of SGLT2 over SGLT1 is critical for minimizing adverse side effects associated with SGLT1 inhibition. A library of C-glucosyl dihydrochalcones and their dihydrochalcone and chalcone precursors was synthesized and tested as SGLT1/SGLT2 inhibitors using a cell-based fluorescence assay of glucose uptake. The most potent inhibitors of SGLT2 (IC50 = 9-23 nM) were considerably weaker inhibitors of SGLT1 (IC50 = 10-19 μM). They showed no effect on the sodium independent GLUT family of glucose transporters, and the most potent ones were not acutely toxic to cultured cells. The interaction of a C-glucosyl dihydrochalcone with a POPC membrane was modeled computationally, providing evidence that it is not a pan-assay interference compound. These results point toward the discovery of structures that are potent and highly selective inhibitors of SGLT2.
|
Inhibition of human SGLT2 expressed in CHO cells assessed as decrease in uptake of [14C]AMG after 120 mins by TopCount method
|
Homo sapiens
|
1.5
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor (HSK0935) for the Treatment of Type 2 Diabetes.
Year : 2017
Volume : 60
Issue : 10
First Page : 4173
Last Page : 4184
Authors : Li Y, Shi Z, Chen L, Zheng S, Li S, Xu B, Liu Z, Liu J, Deng C, Ye F.
Abstract : A new class of potent and highly selective SGLT2 inhibitors is disclosed. Compound 31 (HSK0935) demonstrated excellent hSGLT2 inhibition of 1.3 nM and a high hSGLT1/hSGLT2 selectivity of 843-fold. It showed robust urinary glucose excretion in Sprague-Dawley (SD) rats and affected more urinary glucose excretion in Rhesus monkeys. Finally, an efficient synthetic route has been developed featuring a ring-closing cascade reaction to incorporate a double ketal 1-methoxy-6,8-dioxabicyclo[3.2.1]octane ring system.
|
Inhibition of human SGLT1 expressed in CHO cells assessed as decrease in uptake of [14C]AMG after 120 mins by TopCount method
|
Homo sapiens
|
629.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor (HSK0935) for the Treatment of Type 2 Diabetes.
Year : 2017
Volume : 60
Issue : 10
First Page : 4173
Last Page : 4184
Authors : Li Y, Shi Z, Chen L, Zheng S, Li S, Xu B, Liu Z, Liu J, Deng C, Ye F.
Abstract : A new class of potent and highly selective SGLT2 inhibitors is disclosed. Compound 31 (HSK0935) demonstrated excellent hSGLT2 inhibition of 1.3 nM and a high hSGLT1/hSGLT2 selectivity of 843-fold. It showed robust urinary glucose excretion in Sprague-Dawley (SD) rats and affected more urinary glucose excretion in Rhesus monkeys. Finally, an efficient synthetic route has been developed featuring a ring-closing cascade reaction to incorporate a double ketal 1-methoxy-6,8-dioxabicyclo[3.2.1]octane ring system.
|
Inhibition of full-length human SGLT2 expressed in CHO cells assessed as decrease in [14C]-methyl alpha-D-glucopyranoside uptake after 1 hr by liquid scintillation counting method
|
Homo sapiens
|
1.05
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and biological evaluation of 6-hydroxyl C-aryl glucoside derivatives as novel sodium glucose co-transporter 2 (SGLT2) inhibitors.
Year : 2018
Volume : 28
Issue : 12
First Page : 2201
Last Page : 2205
Authors : Zhao X, Sun B, Zheng H, Liu J, Qian L, Wang X, Lou H.
Abstract : The sodium glucose co-transporter 2 (SGLT2) was considered as an important target for the treatment of type 2 diabetes mellitus in recent years. This report describes the design and synthesis of a series of novel SGLT2 inhibitors (11a-17a) as well as their dehydrate dihydrofuran derivatives (11b-17b), which were prepared by Mitsunobu reaction. Their SGLT2 inhibitory activity was also evaluated, and 16a and 17a were found to be the most potent compounds with IC50 values of 0.63 and 0.81 nM, respectively. However, all the dehydrate derivatives lose the SGLT2 inhibitory activity, with inhibition percentage no more than 66.5% at the concentration of 0.5 μM, which might because of the configuration inversion at C-2 of glucose. In conclusion, the present study improves understanding of the SAR of SGLT2 inhibitors, and provided more information that could be applied to design new molecules.
|
Inhibition of full-length human SGLT2 expressed in CHO cells assessed as decrease in [14C]-methyl alpha-D-glucopyranoside uptake at 0.5 uM after 1 hr by liquid scintillation counting method
|
Homo sapiens
|
103.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and biological evaluation of 6-hydroxyl C-aryl glucoside derivatives as novel sodium glucose co-transporter 2 (SGLT2) inhibitors.
Year : 2018
Volume : 28
Issue : 12
First Page : 2201
Last Page : 2205
Authors : Zhao X, Sun B, Zheng H, Liu J, Qian L, Wang X, Lou H.
Abstract : The sodium glucose co-transporter 2 (SGLT2) was considered as an important target for the treatment of type 2 diabetes mellitus in recent years. This report describes the design and synthesis of a series of novel SGLT2 inhibitors (11a-17a) as well as their dehydrate dihydrofuran derivatives (11b-17b), which were prepared by Mitsunobu reaction. Their SGLT2 inhibitory activity was also evaluated, and 16a and 17a were found to be the most potent compounds with IC50 values of 0.63 and 0.81 nM, respectively. However, all the dehydrate derivatives lose the SGLT2 inhibitory activity, with inhibition percentage no more than 66.5% at the concentration of 0.5 μM, which might because of the configuration inversion at C-2 of glucose. In conclusion, the present study improves understanding of the SAR of SGLT2 inhibitors, and provided more information that could be applied to design new molecules.
|
Inhibition of human SGLT2 expressed in CHO cells assessed as reduction in [14C]AMG uptake after 1 hr by microbeta counting method
|
Homo sapiens
|
2.0
nM
|
|
Journal : Eur J Med Chem
Title : Identification of an oxime-containing C-glucosylarene as a potential inhibitor of sodium-dependent glucose co-transporter 2.
Year : 2018
Volume : 143
First Page : 611
Last Page : 620
Authors : Yuan MC, Yeh TK, Chen CT, Song JS, Huang YC, Hsieh TC, Huang CY, Huang YL, Wang MH, Wu SH, Yao CH, Chao YS, Lee JC.
Abstract : Treatment of hyperglycemia with drugs that block renal glucose reabsorption via inhibition of sodium-dependent glucose cotransporter 2 (SGLT2) is a novel approach to diabetes management. In this study, twenty-seven aryl C-glycosides bearing a C=N/C-N linkage at the glucosyl C6 position were designed, synthesized and evaluated for their inhibitory activity against human SGLT2 (hSGLT2). Compounds with good hSGLT2 inhibition were further investigated to determine their selectivity over hSGLT1. Of these, five representative aryl C-glycosides were chosen for pharmacokinetic analysis. Oxime 2a was determined to have the most promising pharmacokinetic properties and was selected for in vivo glucosuria and plasma glucose level studies, which found it to exhibit comparable efficacy to dapagliflozin (1). Furthermore, 2a was not found to exhibit either significant cytotoxicity (CC50 > 50 μM) or human ether-a-go-go related gene (hERG) inhibition (2% inhibition at 10 μM). Taken together, these efforts culminated in the discovery of oxime 2a as a potential SGLT2 inhibitor.
|
Inhibition of human SGLT1 expressed in CHO cells assessed as reduction in [14C]AMG uptake after 1 hr by microbeta counting method
|
Homo sapiens
|
860.0
nM
|
|
Journal : Eur J Med Chem
Title : Identification of an oxime-containing C-glucosylarene as a potential inhibitor of sodium-dependent glucose co-transporter 2.
Year : 2018
Volume : 143
First Page : 611
Last Page : 620
Authors : Yuan MC, Yeh TK, Chen CT, Song JS, Huang YC, Hsieh TC, Huang CY, Huang YL, Wang MH, Wu SH, Yao CH, Chao YS, Lee JC.
Abstract : Treatment of hyperglycemia with drugs that block renal glucose reabsorption via inhibition of sodium-dependent glucose cotransporter 2 (SGLT2) is a novel approach to diabetes management. In this study, twenty-seven aryl C-glycosides bearing a C=N/C-N linkage at the glucosyl C6 position were designed, synthesized and evaluated for their inhibitory activity against human SGLT2 (hSGLT2). Compounds with good hSGLT2 inhibition were further investigated to determine their selectivity over hSGLT1. Of these, five representative aryl C-glycosides were chosen for pharmacokinetic analysis. Oxime 2a was determined to have the most promising pharmacokinetic properties and was selected for in vivo glucosuria and plasma glucose level studies, which found it to exhibit comparable efficacy to dapagliflozin (1). Furthermore, 2a was not found to exhibit either significant cytotoxicity (CC50 > 50 μM) or human ether-a-go-go related gene (hERG) inhibition (2% inhibition at 10 μM). Taken together, these efforts culminated in the discovery of oxime 2a as a potential SGLT2 inhibitor.
|
Inhibition of SGLT2 (unknown origin)
|
Homo sapiens
|
1.1
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of nitric oxide releasing derivatives of dapagliflozin as potential anti-diabetic and anti-thrombotic agents.
Year : 2018
Volume : 26
Issue : 14
First Page : 3947
Last Page : 3952
Authors : Li Z, Xu X, Deng L, Liao R, Liang R, Zhang B, Zhang L.
Abstract : The cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Therefore, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of NO donor and SGLT2 inhibitor were design to achieve dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the preferred hybrid 2 exhibited moderate SGLT2 inhibitory effects and anti-platelet aggregation activities, and its anti-platelet effect mediated by NO was also confirmed in the presence of NO scavenger. Moreover, compound 2 revealed significantly hypoglycemic effects and excretion of urinary glucose during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 2, is expected as a potential candidate for the intervention of cardiovascular complications in T2DM.
|
Inhibition of human SGLT2 expressed in HEK293 cells assessed as decrease in [14C]-AMG uptake preincubated for 10 mins followed by [14C]-AMG addition and measured after 2 hrs by liquid scintillation counting method
|
Homo sapiens
|
1.4
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of nitric oxide releasing derivatives of dapagliflozin as potential anti-diabetic and anti-thrombotic agents.
Year : 2018
Volume : 26
Issue : 14
First Page : 3947
Last Page : 3952
Authors : Li Z, Xu X, Deng L, Liao R, Liang R, Zhang B, Zhang L.
Abstract : The cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Therefore, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of NO donor and SGLT2 inhibitor were design to achieve dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the preferred hybrid 2 exhibited moderate SGLT2 inhibitory effects and anti-platelet aggregation activities, and its anti-platelet effect mediated by NO was also confirmed in the presence of NO scavenger. Moreover, compound 2 revealed significantly hypoglycemic effects and excretion of urinary glucose during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 2, is expected as a potential candidate for the intervention of cardiovascular complications in T2DM.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
11.91
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of human SGLT2
|
Homo sapiens
|
1.12
nM
|
|
Journal : Eur J Med Chem
Title : Synthetic strategy and SAR studies of C-glucoside heteroaryls as SGLT2 inhibitor: A review.
Year : 2019
Volume : 184
First Page : 111773
Last Page : 111773
Authors : Haider K, Pathak A, Rohilla A, Haider MR, Ahmad K, Yar MS.
Abstract : Gliflozins constitute an important class of compounds useful as sodium glucose co-transporter (SGLT2) inhibitors to treat type-II diabetes. They act by blocking sodium-glucose transport protein 2 which is responsible for re-absorption of glucose in the proximal convoluted tubule (PCT) of kidney and thus its inhibition reduces blood glucose level. There are a number of gliflozins which have been approved by drug regulatory bodies like FDA, EMA and PMDA whereas some others are in pipeline in their late developmental phases. The present review article offers a detailed account of synthetic strategies employed for the synthesis, alternate synthetic routes along with Structure Activity Relationship (SAR) studies of well-established as well as newly developed SGLT2 inhibitors.
|
Inhibition of SGLT2 (unknown origin)
|
Homo sapiens
|
1.1
nM
|
|
Journal : J Med Chem
Title : The Race to Bash NASH: Emerging Targets and Drug Development in a Complex Liver Disease.
Year : 2020
Volume : 63
Issue : 10
First Page : 5031
Last Page : 5073
Authors : Romero FA, Jones CT, Xu Y, Fenaux M, Halcomb RL.
Abstract : Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) characterized by liver steatosis, inflammation, and hepatocellular damage. NASH is a serious condition that can progress to cirrhosis, liver failure, and hepatocellular carcinoma. The association of NASH with obesity, type 2 diabetes mellitus, and dyslipidemia has led to an emerging picture of NASH as the liver manifestation of metabolic syndrome. Although diet and exercise can dramatically improve NASH outcomes, significant lifestyle changes can be challenging to sustain. Pharmaceutical therapies could be an important addition to care, but currently none are approved for NASH. Here, we review the most promising targets for NASH treatment, along with the most advanced therapeutics in development. These include targets involved in metabolism (e.g., sugar, lipid, and cholesterol metabolism), inflammation, and fibrosis. Ultimately, combination therapies addressing multiple aspects of NASH pathogenesis are expected to provide benefit for patients.
|
Inhibition of human full length SGLT2 expressed in NIH3T3 cells measured after 1 hr in presence of [14C]-methyl-alpha -D-glucopyranoside by scintillation counter method
|
Homo sapiens
|
8.3
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of 6-deoxy O-spiroketal C-arylglucosides as novel renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.
Year : 2019
Volume : 180
First Page : 398
Last Page : 416
Authors : Wang Y, Lou Y, Wang J, Li D, Chen H, Zheng T, Xia C, Song X, Dong T, Li J, Li J, Liu H.
Abstract : In this work, aiming at finding a novel, potent, and selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor with good pharmacokinetic profiles for the treatment of diabetes, we focus on modifying the sugar moiety of SGLT2 inhibitors, which dominates the binding with glucose binding site of hSGLT, via removing the C-6 hydroxy group to adjust the physicochemical properties and target-recognition manners of SGLT2 inhibitors. In addition, tofogliflozin containing a special O-spiroketal C-arylglucoside scaffold, displayed good efficacy and bioavailability both in animals and in humans. Therefore, a series of 6-deoxy O-spiroketal C-arylglucosides as novel SGLT2 inhibitors were designed, synthesized, and evaluated in this work. The structure-activity relationship (SAR) research on this novel series and a comprehensive in vitro and in vivo biological evaluation afforded compound 39 with high in vitro hSGLT2 inhibitory activity (IC<sub>50</sub> = 4.5 nM), good pharmacokinetic profiles, and more remarkable efficacy in C57BL/6J mice and Sprague-Dawley rats than marketed drug tofogliflozin.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
11.09
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
13.81
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.14
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.11
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.11
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.14
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
