|
Percent inhibition of glucose rise, following 100 mg/kg oral dose in fasted nondiabetic rats
|
Rattus norvegicus
|
41.0
%
|
|
Journal : J. Med. Chem.
Title : Carbohydrate biguanides as potential hypoglycemic agents.
Year : 1989
Volume : 32
Issue : 9
First Page : 2110
Last Page : 2116
Authors : Reitz AB, Tuman RW, Marchione CS, Jordan AD, Bowden CR, Maryanoff BE.
Abstract : A series of monosaccharides containing a biguanide functionality was prepared and evaluated for hypoglycemic activity. Among the analogues prepared were those involving D-glucose substituted on the 6- or 1-position (19 and 24), D-galactose substituted on the 6-position (7), and D-arabinose (31). The target compounds were evaluated in a modified rat glucose-tolerance test (oral glucose load/oral drug, 100 mg/kg). Compounds 8 [6-biguanidino-1,2:3,5-bis-O-(1-methylethylidene)-6-deoxy-al pha-D- glucofuranose] and 23 [methyl 6-biguanidino-6-deoxy-2,3,4-O-tribenzyl-alpha-D-glucopyra nos ide] were the most active, exhibiting nearly equivalent hypoglycemic activity to that of phenformin (1) and metformin (2), as measured by the inhibition of the rise of blood glucose. Compound 31 was somewhat less active with 26% inhibition, as compared to 64% inhibition with 1 and 41% inhibition with 2.
|
Inhibition of DPP4 at 10 mM
|
None
|
12.7
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of dipeptidyl peptidase-IV (DPP-IV) by atorvastatin.
Year : 2008
Volume : 18
Issue : 2
First Page : 479
Last Page : 484
Authors : Taldone T, Zito SW, Talele TT.
Abstract : Dipeptidyl peptidase-IV (DPP-IV) is an enzyme responsible for the inactivation of the glucoregulatory incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). In this report, we show that the hypolipidemic agent atorvastatin is a competitive inhibitor of porcine DPP-IV in vitro, with K(i)=57.8+/-2.3 microM. These results may have implications in the development of novel DPP-IV inhibitors based on the use of atorvastatin as a lead compound for the treatment of type 2 diabetes.
|
Inhibition of DPP4 at 30 mM
|
None
|
21.9
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of dipeptidyl peptidase-IV (DPP-IV) by atorvastatin.
Year : 2008
Volume : 18
Issue : 2
First Page : 479
Last Page : 484
Authors : Taldone T, Zito SW, Talele TT.
Abstract : Dipeptidyl peptidase-IV (DPP-IV) is an enzyme responsible for the inactivation of the glucoregulatory incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). In this report, we show that the hypolipidemic agent atorvastatin is a competitive inhibitor of porcine DPP-IV in vitro, with K(i)=57.8+/-2.3 microM. These results may have implications in the development of novel DPP-IV inhibitors based on the use of atorvastatin as a lead compound for the treatment of type 2 diabetes.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
19.6
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Antihyperglycemic activity in rat sucrose loaded model assessed as reduction of blood glucose level at 100 mg/kg, po
|
Rattus norvegicus
|
42.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and docking studies on phenoxy-3-piperazin-1-yl-propan-2-ol derivatives as protein tyrosine phosphatase 1B inhibitors.
Year : 2010
Volume : 20
Issue : 19
First Page : 5732
Last Page : 5734
Authors : Gupta S, Pandey G, Rahuja N, Srivastava AK, Saxena AK.
Abstract : A series of substituted phenoxy-3-piperazin-1-yl-propan-2-ols has been synthesized and evaluated for PTP1B inhibitory activity in vitro and for antidiabetic activity in vivo. Two molecules viz. 4a and 5b showed PTP1B inhibition of 31.58% and 35.90% at 100 μM concentration. The compound 4a also showed 40.3% normalization of plasma glucose levels at 100mg/kg in Sugar-loaded model (SLM) and 32% activity in Streptozodocin model (STZ). The docking studies of these molecules revealed that hydrogen bond formation with Arg221 is important for activity.
|
Antihyperglycemic activity in rat streptozotocin-induced diabetic model assessed as reduction of blood glucose level at 100 mg/kg, po after 5 hrs
|
Rattus norvegicus
|
28.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and docking studies on phenoxy-3-piperazin-1-yl-propan-2-ol derivatives as protein tyrosine phosphatase 1B inhibitors.
Year : 2010
Volume : 20
Issue : 19
First Page : 5732
Last Page : 5734
Authors : Gupta S, Pandey G, Rahuja N, Srivastava AK, Saxena AK.
Abstract : A series of substituted phenoxy-3-piperazin-1-yl-propan-2-ols has been synthesized and evaluated for PTP1B inhibitory activity in vitro and for antidiabetic activity in vivo. Two molecules viz. 4a and 5b showed PTP1B inhibition of 31.58% and 35.90% at 100 μM concentration. The compound 4a also showed 40.3% normalization of plasma glucose levels at 100mg/kg in Sugar-loaded model (SLM) and 32% activity in Streptozodocin model (STZ). The docking studies of these molecules revealed that hydrogen bond formation with Arg221 is important for activity.
|
Antihyperglycemic activity in rat streptozotocin-induced diabetic model assessed as reduction of blood glucose level at 100 mg/kg, po after 24 hrs
|
Rattus norvegicus
|
29.8
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and docking studies on phenoxy-3-piperazin-1-yl-propan-2-ol derivatives as protein tyrosine phosphatase 1B inhibitors.
Year : 2010
Volume : 20
Issue : 19
First Page : 5732
Last Page : 5734
Authors : Gupta S, Pandey G, Rahuja N, Srivastava AK, Saxena AK.
Abstract : A series of substituted phenoxy-3-piperazin-1-yl-propan-2-ols has been synthesized and evaluated for PTP1B inhibitory activity in vitro and for antidiabetic activity in vivo. Two molecules viz. 4a and 5b showed PTP1B inhibition of 31.58% and 35.90% at 100 μM concentration. The compound 4a also showed 40.3% normalization of plasma glucose levels at 100mg/kg in Sugar-loaded model (SLM) and 32% activity in Streptozodocin model (STZ). The docking studies of these molecules revealed that hydrogen bond formation with Arg221 is important for activity.
|
Antihyperglycemic activity in Charles Foster/Wistar albino rat assessed as reduction in blood glucose level at 100 mg/kg, po administered 30 mins before sucrose challenge
|
Rattus norvegicus
|
12.9
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design and synthesis of 3,5-diarylisoxazole derivatives as novel class of anti-hyperglycemic and lipid lowering agents.
Year : 2009
Volume : 17
Issue : 14
First Page : 5285
Last Page : 5292
Authors : Kumar A, Maurya RA, Sharma S, Ahmad P, Singh AB, Tamrakar AK, Srivastava AK.
Abstract : We have designed 1,3-disubstituted-5-membered heteroaromatic ring system as a common core motif from known anti-hyperglycemic agents. Designed compounds were synthesized and screened for in vivo anti-hyperglycemic activity in sucrose loaded model (SLM), sucrose-challenged streptozotocin-induced diabetic rat model (STZ-S) as well as db/db mice model. Some of the synthesized compounds showed promising in vivo anti-hyperglycemic as well as moderate lipid lowering activity. Synthesized Compounds were screened in various in vitro models of type-2 diabeties such as DPP-4, PTP1B and PPARgamma to know the mechanism of their anti-hyperglycemic action. None of the synthesized compounds showed DPP-4 inhibitory as well as PPARgamma activity. These compounds have shown promising PTP-1B inhibitory activity there by revealing that compounds exhibit anti-diabetic activity by PTP1B pathway.
|
Antihyperglycemic activity against sucrose challenged streptozotocin-induced diabetic Sprague-Dawley albino rat assessed as reduction in blood glucose level at 100 mg/kg, po administered 30 mins before sucrose challenge measured after 5 hrs
|
Rattus norvegicus
|
19.1
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design and synthesis of 3,5-diarylisoxazole derivatives as novel class of anti-hyperglycemic and lipid lowering agents.
Year : 2009
Volume : 17
Issue : 14
First Page : 5285
Last Page : 5292
Authors : Kumar A, Maurya RA, Sharma S, Ahmad P, Singh AB, Tamrakar AK, Srivastava AK.
Abstract : We have designed 1,3-disubstituted-5-membered heteroaromatic ring system as a common core motif from known anti-hyperglycemic agents. Designed compounds were synthesized and screened for in vivo anti-hyperglycemic activity in sucrose loaded model (SLM), sucrose-challenged streptozotocin-induced diabetic rat model (STZ-S) as well as db/db mice model. Some of the synthesized compounds showed promising in vivo anti-hyperglycemic as well as moderate lipid lowering activity. Synthesized Compounds were screened in various in vitro models of type-2 diabeties such as DPP-4, PTP1B and PPARgamma to know the mechanism of their anti-hyperglycemic action. None of the synthesized compounds showed DPP-4 inhibitory as well as PPARgamma activity. These compounds have shown promising PTP-1B inhibitory activity there by revealing that compounds exhibit anti-diabetic activity by PTP1B pathway.
|
Antihyperglycemic activity against sucrose challenged streptozotocin-induced diabetic Sprague-Dawley albino rat assessed as reduction in blood glucose level at 100 mg/kg, po administered 30 mins before sucrose challenge measured after 24 hrs
|
Rattus norvegicus
|
20.2
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design and synthesis of 3,5-diarylisoxazole derivatives as novel class of anti-hyperglycemic and lipid lowering agents.
Year : 2009
Volume : 17
Issue : 14
First Page : 5285
Last Page : 5292
Authors : Kumar A, Maurya RA, Sharma S, Ahmad P, Singh AB, Tamrakar AK, Srivastava AK.
Abstract : We have designed 1,3-disubstituted-5-membered heteroaromatic ring system as a common core motif from known anti-hyperglycemic agents. Designed compounds were synthesized and screened for in vivo anti-hyperglycemic activity in sucrose loaded model (SLM), sucrose-challenged streptozotocin-induced diabetic rat model (STZ-S) as well as db/db mice model. Some of the synthesized compounds showed promising in vivo anti-hyperglycemic as well as moderate lipid lowering activity. Synthesized Compounds were screened in various in vitro models of type-2 diabeties such as DPP-4, PTP1B and PPARgamma to know the mechanism of their anti-hyperglycemic action. None of the synthesized compounds showed DPP-4 inhibitory as well as PPARgamma activity. These compounds have shown promising PTP-1B inhibitory activity there by revealing that compounds exhibit anti-diabetic activity by PTP1B pathway.
|
Antihyperglycemic activity in C57BL/Ks db/db mouse assessed as reduction in blood glucose level measured after 3 days relative to control
|
Mus musculus
|
11.2
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design and synthesis of 3,5-diarylisoxazole derivatives as novel class of anti-hyperglycemic and lipid lowering agents.
Year : 2009
Volume : 17
Issue : 14
First Page : 5285
Last Page : 5292
Authors : Kumar A, Maurya RA, Sharma S, Ahmad P, Singh AB, Tamrakar AK, Srivastava AK.
Abstract : We have designed 1,3-disubstituted-5-membered heteroaromatic ring system as a common core motif from known anti-hyperglycemic agents. Designed compounds were synthesized and screened for in vivo anti-hyperglycemic activity in sucrose loaded model (SLM), sucrose-challenged streptozotocin-induced diabetic rat model (STZ-S) as well as db/db mice model. Some of the synthesized compounds showed promising in vivo anti-hyperglycemic as well as moderate lipid lowering activity. Synthesized Compounds were screened in various in vitro models of type-2 diabeties such as DPP-4, PTP1B and PPARgamma to know the mechanism of their anti-hyperglycemic action. None of the synthesized compounds showed DPP-4 inhibitory as well as PPARgamma activity. These compounds have shown promising PTP-1B inhibitory activity there by revealing that compounds exhibit anti-diabetic activity by PTP1B pathway.
|
Increase in glucose consumption in insulin-resistant human HepG2 cells after 24 hrs
|
Homo sapiens
|
270.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological activity of novel tiliroside derivants.
Year : 2011
Volume : 46
Issue : 10
First Page : 5189
Last Page : 5195
Authors : Qin N, Li CB, Jin MN, Shi LH, Duan HQ, Niu WY.
Abstract : A series of new tiliroside derivatives were synthesized and characterized by analytical (1)H NMR, (13)C NMR and mass spectrometry. All of the compounds were evaluated for anti-diabetic properties in vitro using HepG2 cells. Compounds 3c, 3d, and 3i-l caused significant enhancements in glucose consumption by insulin-resistant HepG2 cells compared with control cells and cells that were exposed to metformin (an anti-diabetic drug). Moreover, compound 3l significantly activated adenosine 5'-monophosphate-activated protein kinase activity and reduced acetyl-CoA carboxylase activity. Thus, the tiliroside derivative 3l offers potential to be developed as a new approach for treating type II diabetes.
|
Inhibition of mammosphere formation in human MDA-MB-231 cells at 5 mM after 7 days by inverted phase-contrast microscopy
|
Homo sapiens
|
41.4
%
|
|
Journal : Bioorg. Med. Chem.
Title : Novel epigallocatechin gallate (EGCG) analogs activate AMP-activated protein kinase pathway and target cancer stem cells.
Year : 2012
Volume : 20
Issue : 9
First Page : 3031
Last Page : 3037
Authors : Chen D, Pamu S, Cui Q, Chan TH, Dou QP.
Abstract : AMP-activated protein kinase (AMPK) is a critical monitor of cellular energy status and also controls processes related to tumor development, including cell cycle progression, protein synthesis, cell growth and survival. Therefore AMPK as an anti-cancer target has received intensive attention recently. It has been reported that the anti-diabetic drug metformin and some natural compounds, such as quercetin, genistein, capsaicin and green tea polyphenol epigallocatechin gallate (EGCG), can activate AMPK and inhibit cancer cell growth. Indeed, natural products have been the most productive source of leads for the development of anti-cancer drugs but perceived disadvantages, such as low bioavailability and week potency, have limited their development and use in the clinic. In this study we demonstrated that synthetic EGCG analogs 4 and 6 were more potent AMPK activators than metformin and EGCG. Activation of AMPK by these EGCG analogs resulted in inhibition of cell proliferation, up-regulation of the cyclin-dependent kinase inhibitor p21, down-regulation of mTOR pathway, and suppression of stem cell population in human breast cancer cells. Our findings suggest that novel potent and specific AMPK activators can be discovered from natural and synthetic sources that have potential to be used for anti-cancer therapy in the clinic.
|
Inhibition of mammosphere formation in human MDA-MB-231 cells at 10 mM after 7 days by inverted phase-contrast microscopy
|
Homo sapiens
|
67.6
%
|
|
Journal : Bioorg. Med. Chem.
Title : Novel epigallocatechin gallate (EGCG) analogs activate AMP-activated protein kinase pathway and target cancer stem cells.
Year : 2012
Volume : 20
Issue : 9
First Page : 3031
Last Page : 3037
Authors : Chen D, Pamu S, Cui Q, Chan TH, Dou QP.
Abstract : AMP-activated protein kinase (AMPK) is a critical monitor of cellular energy status and also controls processes related to tumor development, including cell cycle progression, protein synthesis, cell growth and survival. Therefore AMPK as an anti-cancer target has received intensive attention recently. It has been reported that the anti-diabetic drug metformin and some natural compounds, such as quercetin, genistein, capsaicin and green tea polyphenol epigallocatechin gallate (EGCG), can activate AMPK and inhibit cancer cell growth. Indeed, natural products have been the most productive source of leads for the development of anti-cancer drugs but perceived disadvantages, such as low bioavailability and week potency, have limited their development and use in the clinic. In this study we demonstrated that synthetic EGCG analogs 4 and 6 were more potent AMPK activators than metformin and EGCG. Activation of AMPK by these EGCG analogs resulted in inhibition of cell proliferation, up-regulation of the cyclin-dependent kinase inhibitor p21, down-regulation of mTOR pathway, and suppression of stem cell population in human breast cancer cells. Our findings suggest that novel potent and specific AMPK activators can be discovered from natural and synthetic sources that have potential to be used for anti-cancer therapy in the clinic.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
-3.3
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
19.6
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
-4.5
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of PTP1B in Rattus norvegicus (rat) L6 cells assessed as cellular 2-deoxy-D-[U-14C]glucose uptake at 500 uM after 18 hr relative to control
|
Rattus norvegicus
|
30.2
%
|
|
Journal : Med Chem Res
Title : Identification of ZINC02765569: a potent inhibitor of PTP1B by vHTS
Year : 2013
Volume : 22
Issue : 1
First Page : 28
Last Page : 34
Authors : Joshi P, Deora GS, Rathore V, Tanwar O, Rawat AK, Srivastava AK, Jain D
|
Inhibition of PTP1B in Rattus norvegicus (rat) L6 cells assessed as increase in 2-deoxy-D-[U-14C]-glucose uptake at 100 uM after 18 hr relative to control
|
Rattus norvegicus
|
30.2
%
|
|
Journal : Med Chem Res
Title : Molecular modeling and synthesis of ZINC02765569 derivatives as protein tyrosine phosphatase 1B inhibitors: lead optimization study
Year : 2013
Volume : 22
Issue : 4
First Page : 1618
Last Page : 1623
Authors : Joshi P, Deora GS, Rathore V, Rawat AK, Srivastava AK, Jain D
|
Inhibition of PTP1B in Rattus norvegicus (rat) L6 cells assessed as glucose uptake at 50 uM
|
Rattus norvegicus
|
30.2
%
|
|
Journal : Med Chem Res
Title : Design, synthesis and biological evaluation of novel arylidine-malononitrile derivatives as non-carboxylic inhibitors of protein tyrosine phosphatase 1B
Year : 2013
Volume : 22
Issue : 11
First Page : 5344
Last Page : 5348
Authors : Deora GS, Karthikeyan C, Moorthy NSHN, Rathore V, Rawat AK, Tamrakar AK, Srivastava AK, Trivedi P
|
Antihyperglycemic activity in db/db mouse assessed as inhibition of post prandial blood glucose level at 100 mg/kg, po qd administered 15 days by OGTT relative to vehicle-treated control
|
Mus musculus
|
29.7
%
|
|
Journal : Eur. J. Med. Chem.
Title : Thiazolidin-4-one and thiazinan-4-one derivatives analogous to rosiglitazone as potential antihyperglycemic and antidyslipidemic agents.
Year : 2013
Volume : 63
First Page : 611
Last Page : 620
Authors : Raza S, Srivastava SP, Srivastava DS, Srivastava AK, Haq W, Katti SB.
Abstract : A number of thiazolidin-4-one and thiazinan-4-one derivatives were prepared by three component condensation in one pot reaction method. These compounds were evaluated for anti-hyperglycemic activity by in vitro and in vivo assay systems. The compounds with thiazolidin-4-one and thiazinan-4-one moieties exhibited significant anti-hyperglycemic activity. A few compounds (3a, 3b, 4a and 4b) have exhibited both anti-hyperglycemic and anti-dyslipidemic activities. Among them the thiazinan-4-one derivative 4a showed maximal (45%) improvement in oral glucose tolerance test in db/db mice at 30 mg/kg oral dose.
|
Antihyperglycemic activity in db/db mouse assessed as inhibition of post prandial blood glucose level at 100 mg/kg, po qd administered 15 days measured on day 10 by OGTT relative to vehicle-treated control
|
Mus musculus
|
29.1
%
|
|
Journal : Eur. J. Med. Chem.
Title : Thiazolidin-4-one and thiazinan-4-one derivatives analogous to rosiglitazone as potential antihyperglycemic and antidyslipidemic agents.
Year : 2013
Volume : 63
First Page : 611
Last Page : 620
Authors : Raza S, Srivastava SP, Srivastava DS, Srivastava AK, Haq W, Katti SB.
Abstract : A number of thiazolidin-4-one and thiazinan-4-one derivatives were prepared by three component condensation in one pot reaction method. These compounds were evaluated for anti-hyperglycemic activity by in vitro and in vivo assay systems. The compounds with thiazolidin-4-one and thiazinan-4-one moieties exhibited significant anti-hyperglycemic activity. A few compounds (3a, 3b, 4a and 4b) have exhibited both anti-hyperglycemic and anti-dyslipidemic activities. Among them the thiazinan-4-one derivative 4a showed maximal (45%) improvement in oral glucose tolerance test in db/db mice at 30 mg/kg oral dose.
|
Antidiabetic activity in Sprague-Dawley albino rat assessed as inhibition of blood glucose level at 300 mg/kg, ip administered 10 mins prior to oral glucose challenge measured after 10 mins by glucometer relative to control
|
Rattus norvegicus
|
57.1
%
|
|
Journal : Med Chem Res
Title : Synthesis and characterization of 2-(4-((1-alkyl or aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)naphtho[1,2-d]oxazoles for protein tyrosine phosphatase 1B inhibitory activity
Year : 2013
First Page : 1
Last Page : 8
Authors : Madabhushi S, Chinthala N, Kanwal A, Kaur G, Banerjee SK
|
Inhibition of gluconeogenesis in Sprague-Dawley rat hepatocytes assessed as decrease in glucose output at 2 mM after 4 hrs by colorimetric assay relative to control
|
Rattus norvegicus
|
75.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and structure-activity relationship of non-phosphorus-based fructose-1,6-bisphosphatase inhibitors: 2,5-Diphenyl-1,3,4-oxadiazoles.
Year : 2014
Volume : 83
First Page : 15
Last Page : 25
Authors : Liao BR, He HB, Yang LL, Gao LX, Chang L, Tang J, Li JY, Li J, Yang F.
Abstract : With the aim of discovering a novel class of non-phosphorus-based fructose-1,6-bisphosphatase (FBPase) inhibitors, a series of 2,5-diphenyl-1,3,4-oxadiazoles were synthesized based on the hit compound (1) resulting from a high-throughput screening (HTS). Structure-activity relationship (SAR) studies led to the identification of several compounds with comparable inhibitory activities to AMP, the natural allosteric inhibitor of FBPase. Notably, compound 22 and 27b, bearing a terminal carboxyl or 1H-tetrazole, demonstrated remarkable inhibition to gluconeogenesis (GNG). In addition, both inhibition and binding mode to the enzyme were investigated by enzymatic kinetics and in silico experiments for representative compounds 16 and 22.
|
Antihyperglycemic activity in Sprague-Dawley rat hepatocytes assessed as inhibition of glucose production at 2 mM after 6 hrs by glucose oxidase activity assay
|
Rattus norvegicus
|
25.0
%
|
|
Journal : J. Nat. Prod.
Title : Plantadeprate A, a Tricyclic Monoterpene Zwitterionic Guanidium, and Related Derivatives from the Seeds of Plantago depressa.
Year : 2015
Volume : 78
Issue : 11
First Page : 2822
Last Page : 2826
Authors : Zheng XM, Meng FW, Geng F, Qi M, Luo C, Yang L, Wang ZT.
Abstract : Two new alkaloids, plantadeprate A (1) and 1'-(4″-hydroxybutyl)plantagoguanidinic acid (2), along with three known compounds, were isolated from the seeds of Plantago depressa. Their structures were elucidated by physical data analyses including NMR, MS, and electronic circular dichroism (ECD) methods. Plantadeprate A (1), a monoterpene zwitterionic guanidium, possesses a unique 5/5/6-tricyclic ring system. Its absolute configuration was determined by X-ray crystallography and computational methods. Compound 1, plumbagine D (3), and plantagoguanidinic acid (4) exhibited potential antihyperglycemic properties attributed to suppression of hepatic gluconeogenesis with inhibitory rates of 8.2%, 18.5%, and 12.5% at 40 μM, respectively.
|
Hypoglycemic activity in diabetic rat model assessed as decrease in blood glucose level at 100 mg/kg, ig administered for 12 days measured on third day of compound dosing by glucometer relative to control
|
Rattus norvegicus
|
7.86
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Study on the synthesis and biological activities of α-substituted arylacetates derivatives.
Year : 2016
Volume : 26
Issue : 7
First Page : 1715
Last Page : 1719
Authors : Liu J, Chen C, Wu F, Tang J.
Abstract : Anisodamine was isolated from the medicinal herb, it was used in the treatment of gastrointestinal smooth muscle spasm, infective toxic shock and organophosphorus intoxication. But there is no report about anisodamine with α-glucosidase inhibitory activity. In order to find novel α-glucosidase inhibitors, a series of α-substituted arylacetates derivatives have been synthesized based on the active unit of anisodamine. In α-glucosidase assay, compound 9 in Schiff base form and compound 22 in ester form show strong inhibition against α-glucosidase with IC50 value of 46.81μM and 83.76μM, respectively. Compounds 9 and 22 exhibit comparable good antidiabetic activities as commercial drug Glimepiride. In addition, Schiff bases of α-substituted arylacetates show antitumor activities against human cancer cell lines, where compound 9 with thiourea moiety performs the best antitumor activity. We anticipate that our research will provide potential candidate scaffolds for antidiabetic drug design.
|
Hypoglycemic activity in diabetic rat model assessed as decrease in blood glucose level at 100 mg/kg, ig administered for 12 days measured on sixth day of compound dosing by glucometer relative to control
|
Rattus norvegicus
|
7.86
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Study on the synthesis and biological activities of α-substituted arylacetates derivatives.
Year : 2016
Volume : 26
Issue : 7
First Page : 1715
Last Page : 1719
Authors : Liu J, Chen C, Wu F, Tang J.
Abstract : Anisodamine was isolated from the medicinal herb, it was used in the treatment of gastrointestinal smooth muscle spasm, infective toxic shock and organophosphorus intoxication. But there is no report about anisodamine with α-glucosidase inhibitory activity. In order to find novel α-glucosidase inhibitors, a series of α-substituted arylacetates derivatives have been synthesized based on the active unit of anisodamine. In α-glucosidase assay, compound 9 in Schiff base form and compound 22 in ester form show strong inhibition against α-glucosidase with IC50 value of 46.81μM and 83.76μM, respectively. Compounds 9 and 22 exhibit comparable good antidiabetic activities as commercial drug Glimepiride. In addition, Schiff bases of α-substituted arylacetates show antitumor activities against human cancer cell lines, where compound 9 with thiourea moiety performs the best antitumor activity. We anticipate that our research will provide potential candidate scaffolds for antidiabetic drug design.
|
Hypoglycemic activity in diabetic rat model assessed as decrease in blood glucose level at 100 mg/kg, ig administered for 12 days measured on ninth day of compound dosing by glucometer relative to control
|
Rattus norvegicus
|
7.86
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Study on the synthesis and biological activities of α-substituted arylacetates derivatives.
Year : 2016
Volume : 26
Issue : 7
First Page : 1715
Last Page : 1719
Authors : Liu J, Chen C, Wu F, Tang J.
Abstract : Anisodamine was isolated from the medicinal herb, it was used in the treatment of gastrointestinal smooth muscle spasm, infective toxic shock and organophosphorus intoxication. But there is no report about anisodamine with α-glucosidase inhibitory activity. In order to find novel α-glucosidase inhibitors, a series of α-substituted arylacetates derivatives have been synthesized based on the active unit of anisodamine. In α-glucosidase assay, compound 9 in Schiff base form and compound 22 in ester form show strong inhibition against α-glucosidase with IC50 value of 46.81μM and 83.76μM, respectively. Compounds 9 and 22 exhibit comparable good antidiabetic activities as commercial drug Glimepiride. In addition, Schiff bases of α-substituted arylacetates show antitumor activities against human cancer cell lines, where compound 9 with thiourea moiety performs the best antitumor activity. We anticipate that our research will provide potential candidate scaffolds for antidiabetic drug design.
|
Hypoglycemic activity in diabetic rat model assessed as decrease in blood glucose level at 100 mg/kg, ig administered for 12 days measured on twelfth day by glucometer relative to control
|
Rattus norvegicus
|
7.86
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Study on the synthesis and biological activities of α-substituted arylacetates derivatives.
Year : 2016
Volume : 26
Issue : 7
First Page : 1715
Last Page : 1719
Authors : Liu J, Chen C, Wu F, Tang J.
Abstract : Anisodamine was isolated from the medicinal herb, it was used in the treatment of gastrointestinal smooth muscle spasm, infective toxic shock and organophosphorus intoxication. But there is no report about anisodamine with α-glucosidase inhibitory activity. In order to find novel α-glucosidase inhibitors, a series of α-substituted arylacetates derivatives have been synthesized based on the active unit of anisodamine. In α-glucosidase assay, compound 9 in Schiff base form and compound 22 in ester form show strong inhibition against α-glucosidase with IC50 value of 46.81μM and 83.76μM, respectively. Compounds 9 and 22 exhibit comparable good antidiabetic activities as commercial drug Glimepiride. In addition, Schiff bases of α-substituted arylacetates show antitumor activities against human cancer cell lines, where compound 9 with thiourea moiety performs the best antitumor activity. We anticipate that our research will provide potential candidate scaffolds for antidiabetic drug design.
|
Antidiabetic activity in overnight fasted STZ-induced albino Sprague-Dawley rat diabetic model assessed as decrease in blood glucose level at 100 mg/kg, po measured up to 5 hrs
|
Rattus norvegicus
|
25.9
%
|
|
Journal : J Nat Prod
Title : Naturally Occurring Carbazole Alkaloids from Murraya koenigii as Potential Antidiabetic Agents.
Year : 2016
Volume : 79
Issue : 5
First Page : 1276
Last Page : 1284
Authors : Patel OP, Mishra A, Maurya R, Saini D, Pandey J, Taneja I, Raju KS, Kanojiya S, Shukla SK, Srivastava MN, Wahajuddin M, Tamrakar AK, Srivastava AK, Yadav PP.
Abstract : This study identified koenidine (4) as a metabolically stable antidiabetic compound, when evaluated in a rodent type 2 model (leptin receptor-deficient db/db mice), and showed a considerable reduction in the postprandial blood glucose profile with an improvement in insulin sensitivity. Biological studies were directed from the preliminary in vitro evaluation of the effects of isolated carbazole alkaloids (1-6) on glucose uptake and GLUT4 translocation in L6-GLUT4myc myotubes, followed by an investigation of their activity (2-5) in streptozotocin-induced diabetic rats. The effect of koenidine (4) on GLUT4 translocation was mediated by the AKT-dependent signaling pathway in L6-GLUT4myc myotubes. Moreover, in vivo pharmacokinetic studies of compounds 2 and 4 clearly showed that compound 4 was 2.7 times more bioavailable than compound 2, resulting in a superior in vivo efficacy. Therefore, these studies suggested that koenidine (4) may serve as a promising lead natural scaffold for managing insulin resistance and diabetes.
|
Antidiabetic activity in overnight fasted STZ-induced albino Sprague-Dawley rat diabetic model assessed as decrease in blood glucose level at 100 mg/kg, po measured up to 24 hrs
|
Rattus norvegicus
|
36.0
%
|
|
Journal : J Nat Prod
Title : Naturally Occurring Carbazole Alkaloids from Murraya koenigii as Potential Antidiabetic Agents.
Year : 2016
Volume : 79
Issue : 5
First Page : 1276
Last Page : 1284
Authors : Patel OP, Mishra A, Maurya R, Saini D, Pandey J, Taneja I, Raju KS, Kanojiya S, Shukla SK, Srivastava MN, Wahajuddin M, Tamrakar AK, Srivastava AK, Yadav PP.
Abstract : This study identified koenidine (4) as a metabolically stable antidiabetic compound, when evaluated in a rodent type 2 model (leptin receptor-deficient db/db mice), and showed a considerable reduction in the postprandial blood glucose profile with an improvement in insulin sensitivity. Biological studies were directed from the preliminary in vitro evaluation of the effects of isolated carbazole alkaloids (1-6) on glucose uptake and GLUT4 translocation in L6-GLUT4myc myotubes, followed by an investigation of their activity (2-5) in streptozotocin-induced diabetic rats. The effect of koenidine (4) on GLUT4 translocation was mediated by the AKT-dependent signaling pathway in L6-GLUT4myc myotubes. Moreover, in vivo pharmacokinetic studies of compounds 2 and 4 clearly showed that compound 4 was 2.7 times more bioavailable than compound 2, resulting in a superior in vivo efficacy. Therefore, these studies suggested that koenidine (4) may serve as a promising lead natural scaffold for managing insulin resistance and diabetes.
|
Inhibition of human OCT1 expressed in HEK293 cells assessed as decrease in uptake of ASP+ after 2 mins by fluorescence assay
|
Homo sapiens
|
11.1
%
|
|
Journal : J Med Chem
Title : Discovery of Competitive and Noncompetitive Ligands of the Organic Cation Transporter 1 (OCT1; SLC22A1).
Year : 2017
Volume : 60
Issue : 7
First Page : 2685
Last Page : 2696
Authors : Chen EC, Khuri N, Liang X, Stecula A, Chien HC, Yee SW, Huang Y, Sali A, Giacomini KM.
Abstract : Organic cation transporter 1 (OCT1) plays a critical role in the hepatocellular uptake of structurally diverse endogenous compounds and xenobiotics. Here we identified competitive and noncompetitive OCT1-interacting ligands in a library of 1780 prescription drugs by combining in silico and in vitro methods. Ligands were predicted by docking against a comparative model based on a eukaryotic homologue. In parallel, high-throughput screening (HTS) was conducted using the fluorescent probe substrate ASP+ in cells overexpressing human OCT1. Thirty competitive OCT1 ligands, defined as ligands predicted in silico as well as found by HTS, were identified. Of the 167 ligands identified by HTS, five were predicted to potentially cause clinical drug interactions. Finally, virtual screening of 29 332 metabolites predicted 146 competitive OCT1 ligands, of which an endogenous neurotoxin, 1-benzyl-1,2,3,4-tetrahydroisoquinoline, was experimentally validated. In conclusion, by combining docking and in vitro HTS, competitive and noncompetitive ligands of OCT1 can be predicted.
|
Cytotoxicity against human MCF7 cells assessed as inhibition of cell growth measured after 72 hrs by MTT assay
|
Homo sapiens
|
9.9
nM
|
|
Journal : RSC Med Chem
Title : Development of potent CPP6-gemcitabine conjugates against human prostate cancer cell line (PC-3)
Year : 2020
Volume : 11
Issue : 2
First Page : 268
Last Page : 273
Authors : Correia, Cristiana, Xavier, Cristina P. R., Duarte, Diana, Ferreira, Abigail, Moreira, Sara, Vasconcelos, M. Helena, Vale, Nuno
Abstract : Gemcitabine (dFdC) is a nucleoside analogue used in the treatment of various cancers, being a standard treatment for advanced pancreatic cancer. The effect of gemcitabine is severely compromised due to its rapid plasma degradation, systemic toxicity and drug resistance, which restricts its therapeutic efficacy. Our main goal was to develop new active conjugates of dFdC with novel cell-penetrating hexapeptides (CPP6) to facilitate intracellular delivery of this drug. All new peptides were prepared by solid phase peptide synthesis (SPPS), purified and characterized by HPLC and LC-MS. Cell-penetrating peptides (CPP) contain a considerably high ratio of positively charged amino acids, imparting them with cationic character. Tumor cells are characterized by an increased anionic nature of their membrane surface, a property that could be used by CPP to target these cells. The BxPC-3, MCF-7 and PC-3 cancer cell lines were used to evaluate the in vitro cytotoxicity of conjugates and the results showed that conjugating dFdC with CPP6 significantly enhanced cell growth inhibitory activity on PC-3 cells, with IC50 between 14 and 15 nM. These new conjugates have potential to become new therapeutic tools for cancer therapy.
|
Cytotoxicity against human PC-3 cells assessed as inhibition of cell growth measured after 72 hrs by MTT assay
|
Homo sapiens
|
189.0
nM
|
|
Journal : RSC Med Chem
Title : Development of potent CPP6-gemcitabine conjugates against human prostate cancer cell line (PC-3)
Year : 2020
Volume : 11
Issue : 2
First Page : 268
Last Page : 273
Authors : Correia, Cristiana, Xavier, Cristina P. R., Duarte, Diana, Ferreira, Abigail, Moreira, Sara, Vasconcelos, M. Helena, Vale, Nuno
Abstract : Gemcitabine (dFdC) is a nucleoside analogue used in the treatment of various cancers, being a standard treatment for advanced pancreatic cancer. The effect of gemcitabine is severely compromised due to its rapid plasma degradation, systemic toxicity and drug resistance, which restricts its therapeutic efficacy. Our main goal was to develop new active conjugates of dFdC with novel cell-penetrating hexapeptides (CPP6) to facilitate intracellular delivery of this drug. All new peptides were prepared by solid phase peptide synthesis (SPPS), purified and characterized by HPLC and LC-MS. Cell-penetrating peptides (CPP) contain a considerably high ratio of positively charged amino acids, imparting them with cationic character. Tumor cells are characterized by an increased anionic nature of their membrane surface, a property that could be used by CPP to target these cells. The BxPC-3, MCF-7 and PC-3 cancer cell lines were used to evaluate the in vitro cytotoxicity of conjugates and the results showed that conjugating dFdC with CPP6 significantly enhanced cell growth inhibitory activity on PC-3 cells, with IC50 between 14 and 15 nM. These new conjugates have potential to become new therapeutic tools for cancer therapy.
|
Antioxidant activity in STZ-induced diabetic Kunming mouse assessed as reduction in liver MDA level at 80 mg/kg, po administered daily via gavage for 8 weeks and measured at 6 hrs post-final drug dose relative to STZ-treated group
|
Mus musculus
|
43.0
%
|
|
Journal : Eur J Med Chem
Title : Multifunctional agents based on benzoxazolone as promising therapeutic drugs for diabetic nephropathy.
Year : 2021
Volume : 215
First Page : 113269
Last Page : 113269
Authors : Zhang X,Chen H,Lei Y,Zhang X,Xu L,Liu W,Fan Z,Ma Z,Yin Z,Li L,Zhu C,Ma B
Abstract : Diabetic nephropathy (DN) is resulted from activations of polyol pathway and oxidative stress by abnormal metabolism of glucose, and no specific medication is available. We designed a novel class of benzoxazolone derivatives, and a number of individuals were found to have significant antioxidant activity and inhibition of aldose reductase of the key enzyme in the polyol pathway. The outstanding compound (E)-2-(7-(4-hydroxy-3-methoxystyryl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid was identified to reduce urinary proteins in diabetic mice suggesting an alleviation in the diabetic nephropathy, and this was confirmed by kidney hematoxylin-eosin staining. Further investigations showed blood glucose normalization, declined in the polyol pathway and lipid peroxides, and raised glutathione and superoxide dismutase activity. Thus, we suggest a therapeutic function of the compound for DN which could be attributed to the combination of hypoglycemic, aldose reductase inhibition and antioxidant.
|
Reno-protective activity in STZ-induced Kunming mouse model of diabetes assessed as reduction in urinary total protein excretion at 80 mg/kg, po administered daily via gavage for 8 weeks and measured at week 4 relative to control
|
Mus musculus
|
6.0
%
|
|
Journal : Eur J Med Chem
Title : Multifunctional agents based on benzoxazolone as promising therapeutic drugs for diabetic nephropathy.
Year : 2021
Volume : 215
First Page : 113269
Last Page : 113269
Authors : Zhang X,Chen H,Lei Y,Zhang X,Xu L,Liu W,Fan Z,Ma Z,Yin Z,Li L,Zhu C,Ma B
Abstract : Diabetic nephropathy (DN) is resulted from activations of polyol pathway and oxidative stress by abnormal metabolism of glucose, and no specific medication is available. We designed a novel class of benzoxazolone derivatives, and a number of individuals were found to have significant antioxidant activity and inhibition of aldose reductase of the key enzyme in the polyol pathway. The outstanding compound (E)-2-(7-(4-hydroxy-3-methoxystyryl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid was identified to reduce urinary proteins in diabetic mice suggesting an alleviation in the diabetic nephropathy, and this was confirmed by kidney hematoxylin-eosin staining. Further investigations showed blood glucose normalization, declined in the polyol pathway and lipid peroxides, and raised glutathione and superoxide dismutase activity. Thus, we suggest a therapeutic function of the compound for DN which could be attributed to the combination of hypoglycemic, aldose reductase inhibition and antioxidant.
|
Reno-protective activity in STZ-induced Kunming mouse model of diabetes assessed as reduction in urinary total protein excretion at 80 mg/kg, po administered daily via gavage for 8 weeks and measured at week 6 relative to control
|
Mus musculus
|
41.0
%
|
|
Journal : Eur J Med Chem
Title : Multifunctional agents based on benzoxazolone as promising therapeutic drugs for diabetic nephropathy.
Year : 2021
Volume : 215
First Page : 113269
Last Page : 113269
Authors : Zhang X,Chen H,Lei Y,Zhang X,Xu L,Liu W,Fan Z,Ma Z,Yin Z,Li L,Zhu C,Ma B
Abstract : Diabetic nephropathy (DN) is resulted from activations of polyol pathway and oxidative stress by abnormal metabolism of glucose, and no specific medication is available. We designed a novel class of benzoxazolone derivatives, and a number of individuals were found to have significant antioxidant activity and inhibition of aldose reductase of the key enzyme in the polyol pathway. The outstanding compound (E)-2-(7-(4-hydroxy-3-methoxystyryl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid was identified to reduce urinary proteins in diabetic mice suggesting an alleviation in the diabetic nephropathy, and this was confirmed by kidney hematoxylin-eosin staining. Further investigations showed blood glucose normalization, declined in the polyol pathway and lipid peroxides, and raised glutathione and superoxide dismutase activity. Thus, we suggest a therapeutic function of the compound for DN which could be attributed to the combination of hypoglycemic, aldose reductase inhibition and antioxidant.
|
Reno-protective activity in STZ-induced Kunming mouse model of diabetes assessed as reduction in urinary total protein excretion at 80 mg/kg, po administered daily via gavage for 8 weeks and measured at week 8 relative to control
|
Mus musculus
|
18.0
%
|
|
Journal : Eur J Med Chem
Title : Multifunctional agents based on benzoxazolone as promising therapeutic drugs for diabetic nephropathy.
Year : 2021
Volume : 215
First Page : 113269
Last Page : 113269
Authors : Zhang X,Chen H,Lei Y,Zhang X,Xu L,Liu W,Fan Z,Ma Z,Yin Z,Li L,Zhu C,Ma B
Abstract : Diabetic nephropathy (DN) is resulted from activations of polyol pathway and oxidative stress by abnormal metabolism of glucose, and no specific medication is available. We designed a novel class of benzoxazolone derivatives, and a number of individuals were found to have significant antioxidant activity and inhibition of aldose reductase of the key enzyme in the polyol pathway. The outstanding compound (E)-2-(7-(4-hydroxy-3-methoxystyryl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid was identified to reduce urinary proteins in diabetic mice suggesting an alleviation in the diabetic nephropathy, and this was confirmed by kidney hematoxylin-eosin staining. Further investigations showed blood glucose normalization, declined in the polyol pathway and lipid peroxides, and raised glutathione and superoxide dismutase activity. Thus, we suggest a therapeutic function of the compound for DN which could be attributed to the combination of hypoglycemic, aldose reductase inhibition and antioxidant.
|
Inhibition of thrombin-induced platelet aggregation in mouse platelet isolated from C57BL/6J mouse treated at 200 mg/kg, ig twice a day for 7 days by lumi-aggregometer
|
Mus musculus
|
18.5
%
|
|
Journal : Eur J Med Chem
Title : Novel potent antiplatelet thrombotic agent derived from biguanide for ischemic stroke.
Year : 2020
Volume : 200
First Page : 112462
Last Page : 112462
Authors : Xin G,Ming Y,Ji C,Wei Z,Li S,Morris-Natschke SL,Zhang X,Yu K,Li Y,Zhang B,Zhang J,Xing Z,He Y,Chen Z,Yang X,Niu H,Lee KH,Huang W
Abstract : Platelet thrombosis is the main pathogeny resulting in the low curability of ischemic stroke, a leading cause of mortality and disability worldwide. Metformin, a biguanide derivative that is the first-line oral medicine for type 2 diabetes, alleviates the severity of ischemic stroke in diabetic patients and suppresses platelet activation in experimental animal model. However, the clinical implementation of commercial biguanide analogs for stroke related to platelet thrombosis remains challenging due to its weak potency, poor pharmacokinetic characteristics and possible hypoglycemia. Here, twenty-three biguanide derivatives were designed and synthesized based on the principles of bioisosteres. These derivatives were evaluated for the activity of antiplatelet thrombosis in vivo. We found that N-trifluoromethanesulfonyl biguanide derivative, compound b10, uniquely prevented cerebral infarction as well as neuronal function injury, and significantly decrease the mortality rate of ischemic stroke in the middle cerebral artery occlusion mice without significant side effects. We verified that b10 directly inhibited platelets thrombus formation and decreased the compactness of stroke thrombi. Particularly, b10 exhibited good potency to inhibit human platelet activation including platelet aggregation, adhesion, pseudopodia formation, integrin GPIIb/IIIa activation, CD62P expression and clot retraction. Meanwhile, the pharmacokinetics assessment showed that b10 had satisfying pharmacological characteristics including a longer duration and a higher oral absorption ratio than its parent compound. In addition, b10 remarkably ameliorated not only stroke related to platelet thrombosis but also carotid artery thrombus formation. It is concluded that the novel potent antiplatelet thrombotic agent derived from biguanide is a promising candidate for stroke treatment.
