Suresh Giri - Academia.edu (original) (raw)
Papers by Suresh Giri
We have developed a monoclonal antibody (mAb) cocktail (ZRC-3308) comprising of ZRC3308-A7 and ZR... more We have developed a monoclonal antibody (mAb) cocktail (ZRC-3308) comprising of ZRC3308-A7 and ZRC3308-B10 in the ratio 1:1 for COVID-19 treatment. The mAbs were designed to have reduced immune effector functions and increased circulation half-life. mAbs showed good binding affinities to non-competing epitopes on RBD of SARS-CoV-2 spike protein and were found neutralizing SARS-CoV-2 variants B.1, B.1.1.7, B.1.351, B.1.617.2 and B.1.617.2 AY.1 in vitro. The mAb cocktail demonstrated effective prophylactic and therapeutic activity against SARS-CoV-2 infection in Syrian hamsters. The antibody cocktail appears to be a promising candidate for the prophylactic use and for therapy in early COVID-19 cases which have not progressed to severe disease.
Bioorganic & Medicinal Chemistry, 2021
The ever-growing prevalence of Type-2 diabetes in the world has an urgent need for multiple orall... more The ever-growing prevalence of Type-2 diabetes in the world has an urgent need for multiple orally effective agents that can regulate glucose homeostasis. G-Protein coupled receptor 119 (GPR 119) agonists have demonstrated the glucose-dependent insulin secretion and showed beneficial effects on glycemic control in humans and/or relevant animal models. Herein, we describe our efforts towards identification of a potent and oral GPR 119 agonist 13c (ZY-G19), which showed in vitro potency in the cell-based assay and in vivo efficacy without exerting any significant signs of toxicity in relevant animal models.
Scientific Reports, 2020
Insulin resistance and hepatic lipid accumulation constitute the metabolic underpinning of nonalc... more Insulin resistance and hepatic lipid accumulation constitute the metabolic underpinning of nonalcoholic steatohepatitis (NASH). We tested the hypothesis that saroglitazar, a PPAR α/γ agonist would improve NASH in the diet-induced animal model of NAFLD. Mice received chow diet and normal water (CDNW) or high fat western diet and ad lib sugar water (WDSW). After 12 weeks, WDSW fed mice were randomized to receive (1) WDSW alone, (2) WDSW + vehicle, (3) WDSW + pioglitazone or (4) WDSW + saroglitazar for an additional 12 weeks. Compared to mice on WDSW and vehicle controls, mice receiving WDSW + saroglitazar had lower weight, lower HOMA-IR, triglycerides, total cholesterol, and ALT. Saroglitazar improved steatosis, lobular inflammation, hepatocellular ballooning and fibrosis stage. NASH resolved in all mice receiving saroglitazar. These effects were at par with or superior to pioglitazone. Molecular analyses confirmed target engagement and reduced oxidative stress, unfolded protein respo...
Diabetes, 2018
GPR40 is a G-protein-coupled receptor predominantly expressed in pancreatic β-cells. Agonists of ... more GPR40 is a G-protein-coupled receptor predominantly expressed in pancreatic β-cells. Agonists of GPR40 are known to stimulate insulin secretion and reduces circulating glucose levels in a glucose-dependent manner. TAK-875, a GPR40 small molecule agonist developed by Takeda Pharmaceuticals showed antidiabetic efficacy in animals and humans, but its development was terminated in phase 3 due to adverse liver effects. ZYDG2 is a safer GPR40 agonist that has shown desirable profile in preclinical studies. ZYDG2 was identified as a potent and selective agonist for GPR40, exhibiting EC50 of 13 nM and 41 nM for hGPR40, in HEK-293 cell-based Ca2+ mobilization assay and IP1 ELISA assays respectively. It increased insulin secretion and showed dose-dependent improvement in glucose tolerance test in n-STZ Wistar rats, DIO mice and db/db mice. It also showed anti-hyperglycemic effects in rats unresponsive to sulfonylureas. No tachyphylaxis was observed after repeated administration for 15 weeks i...
Diabetes, 2018
Saroglitazar is a novel dual PPARα/γ agonist that shows significant triglyceride-lowering and ins... more Saroglitazar is a novel dual PPARα/γ agonist that shows significant triglyceride-lowering and insulin-sensitizing effects in animal models and humans. Saroglitazar causes insulin sensitization and increases flux of lipids in adipocytes thereby preventing the glucotoxicity and lipotoxicity. It also improves mitochondrial bioenergetics potential and increased the ATP production rate and reduces the expression of pro-inflammatory (TNFα, IL1β and IL6) genes. In this study, we have evaluated the potential of saroglitazar to delay the onset or prevent development of T2DM in db/db mice. The db/db mouse is a widely used model for T2DM and shows progressive changes starting with development of obese phenotype at the age of 4 weeks followed by hyperglycemia and hyperinsulimenic condition between 4-8 weeks of age and hypoinsulinemia accompanied by hyperglycemia at 12-16 weeks of age. Group of male db/db mice were treated with saroglitazar (0.8 and 2.5 mg/kg, p.o.) or metformin (250 mg/kg, p.o....
Liver international : official journal of the International Association for the Study of the Liver, Jan 21, 2017
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common cli... more Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common clinico-pathological conditions that affect millions of patients worldwide. In this study, the efficacy of saroglitazar, a novel PPARα/γ agonist, was assessed in models of NAFLD/NASH. HepG2 cells treated with palmitic acid (PA;0.75 mM) showed decreased expression of various antioxidant biomarkers (SOD1, SOD2, glutathione peroxidase and catalase) and increased expression of inflammatory markers (TNFα, IL1β and IL6). These effects were blocked by saroglitazar, pioglitazone and fenofibrate (all tested at 10μM concentration). Furthermore, these agents reversed PA-mediated changes in mitochondrial dysfunction, ATP production, NFkB phosphorylation and stellate cell activation in HepG2 and HepG2-LX2 Coculture studies. In mice with choline-deficient high-fat diet-induced NASH, saroglitazar reduced hepatic steatosis, inflammation, ballooning and prevented development of fibrosis. It also reduced ser...
Life sciences, 2016
Rosiglitazone (RSZ), a PPARγ agonist was potent efficacious insulin sensitizing blockbuster drug ... more Rosiglitazone (RSZ), a PPARγ agonist was potent efficacious insulin sensitizing blockbuster drug for treatment of Type 2 diabetes mellitus (T2DM) but the benefit of PPARγ activation in congestive heart failure (CHF) was controversial. The present work was planned to study the role of RSZ in diabetic cardiopathy. Zucker fa/fa rats, the genetic model of T2DM were subjected to constriction of suprarenal abdominal aorta so that they represent a combined model of diabetes and cardiopathy. The development cardiopathy was assessed biochemically (plasma BNP and aldosterone levels), using echocardiography and expression angiotensin II receptor type 1a gene in heart and Endothelin-1 gene in aorta. Rats were treated with RSZ and in combination with amiloride for four weeks and were assessed to evaluate the effect of RSZ or amiloride or its combination on antidiabetic activity, adverse or toxic effects and congestive heart failure status. RSZ shows its anti-diabetic effect from 0.3mg/kg dose on...
Journal of pineal research, 2017
Lipid generates reactive oxygen species (ROS) in consequence to mitochondrial fission followed by... more Lipid generates reactive oxygen species (ROS) in consequence to mitochondrial fission followed by inflammation in propagating hepatic fibrosis. The interaction of SIRT1/Mitofusin2 is critical for maintaining mitochondrial integrity and functioning, which is disrupted upon excess lipid infiltration during the progression of steatohepatitis. The complex interplay between hepatic stellate cells and steatotic hepatocytes is critically regulated by extracellular factors including increased circulating free fatty acids during fibrogenesis. Melatonin, a potent antioxidant protects against lipid-mediated mitochondrial ROS generation. Lipotoxicity induces disruption of SIRT1 and Mitofusin2 interaction leading to mitochondrial morphological disintegration in hepatocytes. Further, fragmented mitochondria leads to mitochondrial permeability transition pore opening, cell cycle arrest and apoptosis and melatonin protects against all these lipotoxicity-mediated dysfunctions. These impaired mitocho...
ACS Medicinal Chemistry Letters, 2016
TGR5 is a G protein-coupled receptor (GPCR), activation of which promotes secretion of glucagon-l... more TGR5 is a G protein-coupled receptor (GPCR), activation of which promotes secretion of glucagon-like peptide-1 (GLP-1) and modulates insulin secretion. The 2-thio-imidazole derivative 6g was identified as a novel, potent, and selective TGR5 agonist (hTGR5 EC 50 = 57 pM, mTGR5 = 62 pM) with a favorable pharmacokinetic profile. The compound 6g was found to have potent glucose lowering effects in vivo during an oral glucose tolerance test in DIO C57 mice with ED 50 of 7.9 mg/kg and ED 90 of 29.2 mg/ kg.
Pharmacology Research & Perspectives, 2015
Saroglitazar is a novel nonthiazolidinediones (TZD) and nonfibric acid derivative designed to act... more Saroglitazar is a novel nonthiazolidinediones (TZD) and nonfibric acid derivative designed to act as dual regulator of lipids and glucose metabolism by activating peroxisome proliferator-activated receptors (PPAR). These studies evaluate the efficacy and safety profile of Saroglitazar in preclinical in vitro and in vivo models. The EC 50 values of Saroglitazar assessed in HepG2 cells using PPAR transactivation assay for hPPARa and hPPARc were 0.65 pmol/L and 3 nmol/L, respectively. In db/db mice, 12-day treatment with Saroglitazar (0.01-3 mg/kg per day, orally) caused dose-dependent reductions in serum triglycerides (TG), free fatty acids (FFA), and glucose. The ED 50 for these effects was found to be 0.05, 0.19, and 0.19 mg/kg, respectively with highly significant (91%) reduction in serum insulin and AUC-glucose following oral glucose administration (59%) at 1 mg/kg dose. Significant reduction in serum TG (upto 90%) was also observed in Zucker fa/fa rats, Swiss albino mice, and in high fat-high cholesterol (HF-HC)-fed Golden Syrian hamsters. LDL cholesterol was significantly lowered in hApoB100/hCETP double transgenic mice and HF-HC diet fed Golden Syrian Hamsters. Hyperinsulinemic-Euglycemic clamp study in Zucker fa/fa rats demonstrated potent insulin-sensitizing activity. Saroglitazar also showed a significant decrease in SBP (22 mmHg) and increase (62.1%) in serum adiponectin levels in Zucker fa/fa rats. A 90-day repeated dose comparative study in Wistar rats and marmosets confirmed efficacy (TG lowering) potential of Saroglitazar and has indicated low risk of PPAR-associated side effects in humans. Based on efficacy and safety profile, Saroglitazar appears to have good potential as novel therapeutic agent for treatment of dyslipidemia and diabetes. Abbreviations ACO, acyl-CoA oxidase; ACRP30, adipocyte complement-related protein of 30 kDa; aP2, adipocyte fatty acid-binding protein; CETP, cholesteryl ester transfer protein; FATP, fatty acid transporter protein; GIR, glucose infusion rate; HDL-C, high-density lipoprotein cholesterol; HF-HC, high fat-high cholesterol; IVLTT, intravenous lipid tolerance test; LDL-C, low-density lipoprotein cholesterol; LPL, lipoprotein lipase; NIN, National institute of nutrition; NIRRH, National institute for research in reproductive health; OGTT, oral glucose tolerance test; PPAR, peroxisome proliferator-activated receptors; SAM, swiss albino mice; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides; ZRC, Zydus research centre.
![Research paper thumbnail of ChemInform Abstract: Discovery of a Highly Orally Bioavailable c-5-[6-(4-Methanesulfonyloxyphenyl)hexyl] -2-methyl-1,3-dioxane-r-2-carboxylic Acid (I) as a Potent Hypoglycemic and Hypolipidemic Agent](https://attachments.academia-assets.com/86675021/thumbnails/1.jpg)
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Letters in Drug Design & Discovery, 2010
... as PPAR / Dual Agonists # Harikishore Pingali* ,a,b , Mukul Jain a , Shailesh Shah* ,b , Pank... more ... as PPAR / Dual Agonists # Harikishore Pingali* ,a,b , Mukul Jain a , Shailesh Shah* ,b , Pankaj Makadia a , Pandurang Zaware a , Jeevankumar Jamili a , Kalapatapu VVM Sairam a , Pravin Patil a , Dinesh Suthar a , Suresh Giri a , Harilal Patel a and Pankaj Patel a ...
Journal of Ethnopharmacology, 2009
Ethnopharmacological relevance: We characterized saponins as active constituents from traditional... more Ethnopharmacological relevance: We characterized saponins as active constituents from traditionally used antidiabetic plant Helicteres isora. Aim of the study: To evaluate the changes in the gene expression of the glucose and lipid metabolism regulating genes in C57BL/KsJ-db/db mice. Materials and methods: C57BL/KsJ-db/db mice were divided into four different groups; one diabetic control, the mice in other three groups were treated with methanol extract (100 mg/kg), saponins (100 mg/kg) and pioglitazone (30 mg/kg) for 14 days. After completion of the treatment period biochemical parameters and the expression levels of adipsin, adiponectin, glucose transporter 4 (Glut4), peroxisome proliferator activated receptor gamma (PPAR␥), fatty acid binding protein 4 (FABP4), lipoprotein lipase (LPL) in adipose tissue and for liver RNA samples glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), glucose transporter 2 (Glut2) and acyl-co-enzyme A oxidase (ACOX) were determined by quantitative real time PCR and angiopoeitin like 3 (ANGPTL3), angiopoeitin like 4 (ANGPTL4) and peroxisome proliferator activated receptor alpha (PPAR␣) by semiquantitative reverse transcription PCR. Results: Treatment caused a significant reduction in the serum lipid and glucose levels and increased the expression of adipsin, PPAR␥ and Glut4 while reduced expression of FABP4 and G6Pase, whereas there was no effect on the expression levels of adiponectin, LPL, PEPCK, ACOX, Glut2, ANGPTL3, ANGPTL4 and PPAR␣. Conclusions: Saponins are beneficial for improving hyperlipidemia and hyperglycemia by increasing the gene expression of adipsin, Glut4 and PPAR␥ and reducing the gene expression of the enzyme G6Pase and FABP4 in C57BL/KsJ-db/db mice.
Bioorganic & Medicinal Chemistry Letters, 2010
Bioorganic & Medicinal Chemistry Letters, 2011
A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were... more A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders.
Bioorganic & Medicinal Chemistry Letters, 2011
Bioorganic & Medicinal Chemistry Letters, 2008
A series of novel 1,3-dioxane-2-carboxylic acid derivatives containing alkyl chain tether and sub... more A series of novel 1,3-dioxane-2-carboxylic acid derivatives containing alkyl chain tether and substituted phenyl group as a lipophilic tail have been prepared as agonists of PPARalpha and gamma. c-5-[6-(4-Methanesulfonyloxyphenyl)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid 13c exhibited potent hypoglycemic and lipid lowering activity with high oral bioavailability in animal models.
Bioorganic & Medicinal Chemistry, 2011
A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as ... more A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan agonists. Incorporation of structurally constrained oxime-ether based linker in the chemotype of a potent PPARd selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds 12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPARpan agonistic activity. In vivo, selected test compounds 12a and 17a exhibited significant anti-hyperglycemic and anti-hyperlipidemic activities in relevant animal models. These results support our hypothesis that the introduction of structurally constrained oxime-ether linker between lipophilic tail and acidic head plays an important role in modulating subtype selectivity and subsequently led to the discovery of potent PPAR-pan agonists.
We have developed a monoclonal antibody (mAb) cocktail (ZRC-3308) comprising of ZRC3308-A7 and ZR... more We have developed a monoclonal antibody (mAb) cocktail (ZRC-3308) comprising of ZRC3308-A7 and ZRC3308-B10 in the ratio 1:1 for COVID-19 treatment. The mAbs were designed to have reduced immune effector functions and increased circulation half-life. mAbs showed good binding affinities to non-competing epitopes on RBD of SARS-CoV-2 spike protein and were found neutralizing SARS-CoV-2 variants B.1, B.1.1.7, B.1.351, B.1.617.2 and B.1.617.2 AY.1 in vitro. The mAb cocktail demonstrated effective prophylactic and therapeutic activity against SARS-CoV-2 infection in Syrian hamsters. The antibody cocktail appears to be a promising candidate for the prophylactic use and for therapy in early COVID-19 cases which have not progressed to severe disease.
Bioorganic & Medicinal Chemistry, 2021
The ever-growing prevalence of Type-2 diabetes in the world has an urgent need for multiple orall... more The ever-growing prevalence of Type-2 diabetes in the world has an urgent need for multiple orally effective agents that can regulate glucose homeostasis. G-Protein coupled receptor 119 (GPR 119) agonists have demonstrated the glucose-dependent insulin secretion and showed beneficial effects on glycemic control in humans and/or relevant animal models. Herein, we describe our efforts towards identification of a potent and oral GPR 119 agonist 13c (ZY-G19), which showed in vitro potency in the cell-based assay and in vivo efficacy without exerting any significant signs of toxicity in relevant animal models.
Scientific Reports, 2020
Insulin resistance and hepatic lipid accumulation constitute the metabolic underpinning of nonalc... more Insulin resistance and hepatic lipid accumulation constitute the metabolic underpinning of nonalcoholic steatohepatitis (NASH). We tested the hypothesis that saroglitazar, a PPAR α/γ agonist would improve NASH in the diet-induced animal model of NAFLD. Mice received chow diet and normal water (CDNW) or high fat western diet and ad lib sugar water (WDSW). After 12 weeks, WDSW fed mice were randomized to receive (1) WDSW alone, (2) WDSW + vehicle, (3) WDSW + pioglitazone or (4) WDSW + saroglitazar for an additional 12 weeks. Compared to mice on WDSW and vehicle controls, mice receiving WDSW + saroglitazar had lower weight, lower HOMA-IR, triglycerides, total cholesterol, and ALT. Saroglitazar improved steatosis, lobular inflammation, hepatocellular ballooning and fibrosis stage. NASH resolved in all mice receiving saroglitazar. These effects were at par with or superior to pioglitazone. Molecular analyses confirmed target engagement and reduced oxidative stress, unfolded protein respo...
Diabetes, 2018
GPR40 is a G-protein-coupled receptor predominantly expressed in pancreatic β-cells. Agonists of ... more GPR40 is a G-protein-coupled receptor predominantly expressed in pancreatic β-cells. Agonists of GPR40 are known to stimulate insulin secretion and reduces circulating glucose levels in a glucose-dependent manner. TAK-875, a GPR40 small molecule agonist developed by Takeda Pharmaceuticals showed antidiabetic efficacy in animals and humans, but its development was terminated in phase 3 due to adverse liver effects. ZYDG2 is a safer GPR40 agonist that has shown desirable profile in preclinical studies. ZYDG2 was identified as a potent and selective agonist for GPR40, exhibiting EC50 of 13 nM and 41 nM for hGPR40, in HEK-293 cell-based Ca2+ mobilization assay and IP1 ELISA assays respectively. It increased insulin secretion and showed dose-dependent improvement in glucose tolerance test in n-STZ Wistar rats, DIO mice and db/db mice. It also showed anti-hyperglycemic effects in rats unresponsive to sulfonylureas. No tachyphylaxis was observed after repeated administration for 15 weeks i...
Diabetes, 2018
Saroglitazar is a novel dual PPARα/γ agonist that shows significant triglyceride-lowering and ins... more Saroglitazar is a novel dual PPARα/γ agonist that shows significant triglyceride-lowering and insulin-sensitizing effects in animal models and humans. Saroglitazar causes insulin sensitization and increases flux of lipids in adipocytes thereby preventing the glucotoxicity and lipotoxicity. It also improves mitochondrial bioenergetics potential and increased the ATP production rate and reduces the expression of pro-inflammatory (TNFα, IL1β and IL6) genes. In this study, we have evaluated the potential of saroglitazar to delay the onset or prevent development of T2DM in db/db mice. The db/db mouse is a widely used model for T2DM and shows progressive changes starting with development of obese phenotype at the age of 4 weeks followed by hyperglycemia and hyperinsulimenic condition between 4-8 weeks of age and hypoinsulinemia accompanied by hyperglycemia at 12-16 weeks of age. Group of male db/db mice were treated with saroglitazar (0.8 and 2.5 mg/kg, p.o.) or metformin (250 mg/kg, p.o....
Liver international : official journal of the International Association for the Study of the Liver, Jan 21, 2017
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common cli... more Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common clinico-pathological conditions that affect millions of patients worldwide. In this study, the efficacy of saroglitazar, a novel PPARα/γ agonist, was assessed in models of NAFLD/NASH. HepG2 cells treated with palmitic acid (PA;0.75 mM) showed decreased expression of various antioxidant biomarkers (SOD1, SOD2, glutathione peroxidase and catalase) and increased expression of inflammatory markers (TNFα, IL1β and IL6). These effects were blocked by saroglitazar, pioglitazone and fenofibrate (all tested at 10μM concentration). Furthermore, these agents reversed PA-mediated changes in mitochondrial dysfunction, ATP production, NFkB phosphorylation and stellate cell activation in HepG2 and HepG2-LX2 Coculture studies. In mice with choline-deficient high-fat diet-induced NASH, saroglitazar reduced hepatic steatosis, inflammation, ballooning and prevented development of fibrosis. It also reduced ser...
Life sciences, 2016
Rosiglitazone (RSZ), a PPARγ agonist was potent efficacious insulin sensitizing blockbuster drug ... more Rosiglitazone (RSZ), a PPARγ agonist was potent efficacious insulin sensitizing blockbuster drug for treatment of Type 2 diabetes mellitus (T2DM) but the benefit of PPARγ activation in congestive heart failure (CHF) was controversial. The present work was planned to study the role of RSZ in diabetic cardiopathy. Zucker fa/fa rats, the genetic model of T2DM were subjected to constriction of suprarenal abdominal aorta so that they represent a combined model of diabetes and cardiopathy. The development cardiopathy was assessed biochemically (plasma BNP and aldosterone levels), using echocardiography and expression angiotensin II receptor type 1a gene in heart and Endothelin-1 gene in aorta. Rats were treated with RSZ and in combination with amiloride for four weeks and were assessed to evaluate the effect of RSZ or amiloride or its combination on antidiabetic activity, adverse or toxic effects and congestive heart failure status. RSZ shows its anti-diabetic effect from 0.3mg/kg dose on...
Journal of pineal research, 2017
Lipid generates reactive oxygen species (ROS) in consequence to mitochondrial fission followed by... more Lipid generates reactive oxygen species (ROS) in consequence to mitochondrial fission followed by inflammation in propagating hepatic fibrosis. The interaction of SIRT1/Mitofusin2 is critical for maintaining mitochondrial integrity and functioning, which is disrupted upon excess lipid infiltration during the progression of steatohepatitis. The complex interplay between hepatic stellate cells and steatotic hepatocytes is critically regulated by extracellular factors including increased circulating free fatty acids during fibrogenesis. Melatonin, a potent antioxidant protects against lipid-mediated mitochondrial ROS generation. Lipotoxicity induces disruption of SIRT1 and Mitofusin2 interaction leading to mitochondrial morphological disintegration in hepatocytes. Further, fragmented mitochondria leads to mitochondrial permeability transition pore opening, cell cycle arrest and apoptosis and melatonin protects against all these lipotoxicity-mediated dysfunctions. These impaired mitocho...
ACS Medicinal Chemistry Letters, 2016
TGR5 is a G protein-coupled receptor (GPCR), activation of which promotes secretion of glucagon-l... more TGR5 is a G protein-coupled receptor (GPCR), activation of which promotes secretion of glucagon-like peptide-1 (GLP-1) and modulates insulin secretion. The 2-thio-imidazole derivative 6g was identified as a novel, potent, and selective TGR5 agonist (hTGR5 EC 50 = 57 pM, mTGR5 = 62 pM) with a favorable pharmacokinetic profile. The compound 6g was found to have potent glucose lowering effects in vivo during an oral glucose tolerance test in DIO C57 mice with ED 50 of 7.9 mg/kg and ED 90 of 29.2 mg/ kg.
Pharmacology Research & Perspectives, 2015
Saroglitazar is a novel nonthiazolidinediones (TZD) and nonfibric acid derivative designed to act... more Saroglitazar is a novel nonthiazolidinediones (TZD) and nonfibric acid derivative designed to act as dual regulator of lipids and glucose metabolism by activating peroxisome proliferator-activated receptors (PPAR). These studies evaluate the efficacy and safety profile of Saroglitazar in preclinical in vitro and in vivo models. The EC 50 values of Saroglitazar assessed in HepG2 cells using PPAR transactivation assay for hPPARa and hPPARc were 0.65 pmol/L and 3 nmol/L, respectively. In db/db mice, 12-day treatment with Saroglitazar (0.01-3 mg/kg per day, orally) caused dose-dependent reductions in serum triglycerides (TG), free fatty acids (FFA), and glucose. The ED 50 for these effects was found to be 0.05, 0.19, and 0.19 mg/kg, respectively with highly significant (91%) reduction in serum insulin and AUC-glucose following oral glucose administration (59%) at 1 mg/kg dose. Significant reduction in serum TG (upto 90%) was also observed in Zucker fa/fa rats, Swiss albino mice, and in high fat-high cholesterol (HF-HC)-fed Golden Syrian hamsters. LDL cholesterol was significantly lowered in hApoB100/hCETP double transgenic mice and HF-HC diet fed Golden Syrian Hamsters. Hyperinsulinemic-Euglycemic clamp study in Zucker fa/fa rats demonstrated potent insulin-sensitizing activity. Saroglitazar also showed a significant decrease in SBP (22 mmHg) and increase (62.1%) in serum adiponectin levels in Zucker fa/fa rats. A 90-day repeated dose comparative study in Wistar rats and marmosets confirmed efficacy (TG lowering) potential of Saroglitazar and has indicated low risk of PPAR-associated side effects in humans. Based on efficacy and safety profile, Saroglitazar appears to have good potential as novel therapeutic agent for treatment of dyslipidemia and diabetes. Abbreviations ACO, acyl-CoA oxidase; ACRP30, adipocyte complement-related protein of 30 kDa; aP2, adipocyte fatty acid-binding protein; CETP, cholesteryl ester transfer protein; FATP, fatty acid transporter protein; GIR, glucose infusion rate; HDL-C, high-density lipoprotein cholesterol; HF-HC, high fat-high cholesterol; IVLTT, intravenous lipid tolerance test; LDL-C, low-density lipoprotein cholesterol; LPL, lipoprotein lipase; NIN, National institute of nutrition; NIRRH, National institute for research in reproductive health; OGTT, oral glucose tolerance test; PPAR, peroxisome proliferator-activated receptors; SAM, swiss albino mice; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides; ZRC, Zydus research centre.
Letters in Drug Design & Discovery, 2010
... as PPAR / Dual Agonists # Harikishore Pingali* ,a,b , Mukul Jain a , Shailesh Shah* ,b , Pank... more ... as PPAR / Dual Agonists # Harikishore Pingali* ,a,b , Mukul Jain a , Shailesh Shah* ,b , Pankaj Makadia a , Pandurang Zaware a , Jeevankumar Jamili a , Kalapatapu VVM Sairam a , Pravin Patil a , Dinesh Suthar a , Suresh Giri a , Harilal Patel a and Pankaj Patel a ...
Journal of Ethnopharmacology, 2009
Ethnopharmacological relevance: We characterized saponins as active constituents from traditional... more Ethnopharmacological relevance: We characterized saponins as active constituents from traditionally used antidiabetic plant Helicteres isora. Aim of the study: To evaluate the changes in the gene expression of the glucose and lipid metabolism regulating genes in C57BL/KsJ-db/db mice. Materials and methods: C57BL/KsJ-db/db mice were divided into four different groups; one diabetic control, the mice in other three groups were treated with methanol extract (100 mg/kg), saponins (100 mg/kg) and pioglitazone (30 mg/kg) for 14 days. After completion of the treatment period biochemical parameters and the expression levels of adipsin, adiponectin, glucose transporter 4 (Glut4), peroxisome proliferator activated receptor gamma (PPAR␥), fatty acid binding protein 4 (FABP4), lipoprotein lipase (LPL) in adipose tissue and for liver RNA samples glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), glucose transporter 2 (Glut2) and acyl-co-enzyme A oxidase (ACOX) were determined by quantitative real time PCR and angiopoeitin like 3 (ANGPTL3), angiopoeitin like 4 (ANGPTL4) and peroxisome proliferator activated receptor alpha (PPAR␣) by semiquantitative reverse transcription PCR. Results: Treatment caused a significant reduction in the serum lipid and glucose levels and increased the expression of adipsin, PPAR␥ and Glut4 while reduced expression of FABP4 and G6Pase, whereas there was no effect on the expression levels of adiponectin, LPL, PEPCK, ACOX, Glut2, ANGPTL3, ANGPTL4 and PPAR␣. Conclusions: Saponins are beneficial for improving hyperlipidemia and hyperglycemia by increasing the gene expression of adipsin, Glut4 and PPAR␥ and reducing the gene expression of the enzyme G6Pase and FABP4 in C57BL/KsJ-db/db mice.
Bioorganic & Medicinal Chemistry Letters, 2010
Bioorganic & Medicinal Chemistry Letters, 2011
A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were... more A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders.
Bioorganic & Medicinal Chemistry Letters, 2011
Bioorganic & Medicinal Chemistry Letters, 2008
A series of novel 1,3-dioxane-2-carboxylic acid derivatives containing alkyl chain tether and sub... more A series of novel 1,3-dioxane-2-carboxylic acid derivatives containing alkyl chain tether and substituted phenyl group as a lipophilic tail have been prepared as agonists of PPARalpha and gamma. c-5-[6-(4-Methanesulfonyloxyphenyl)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid 13c exhibited potent hypoglycemic and lipid lowering activity with high oral bioavailability in animal models.
Bioorganic & Medicinal Chemistry, 2011
A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as ... more A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan agonists. Incorporation of structurally constrained oxime-ether based linker in the chemotype of a potent PPARd selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds 12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPARpan agonistic activity. In vivo, selected test compounds 12a and 17a exhibited significant anti-hyperglycemic and anti-hyperlipidemic activities in relevant animal models. These results support our hypothesis that the introduction of structurally constrained oxime-ether linker between lipophilic tail and acidic head plays an important role in modulating subtype selectivity and subsequently led to the discovery of potent PPAR-pan agonists.