suresh giri - Academia.edu (original) (raw)
Papers by suresh giri
ABSTRACTBackground and AimThe pathophysiology of NASH is complex owing to its diverse pathologica... more ABSTRACTBackground and AimThe pathophysiology of NASH is complex owing to its diverse pathological drivers, and until recently, there were no approved drugs for this disease.Tecomella undulatais a popular herbal medicine used to treat hepatosplenomegaly, hepatitis, and obesity. However, the potential role ofTecomella undulatain NASH has not yet been scientifically investigated.Experimental ProcedureMice fed with chow diet and normal water (CDNW) or western diet and sugar water (WDSW) for 12 weeks were randomized to receive vehicle control, Saroglitazar, orTecomella undulatafor an additional 12 weeks. Insulin resistance, lipid profiles, histological analysis, and liver enzymes were assessed. The oxidative stress, ER and inflammatory markers were determined by quantitative RT-PCR (qRT-PCR) and western blot analysis.Results and ConclusionThe administration ofTecomella undulatavia oral gavage lowered body weight, insulin resistance, alanine transaminase (ALT), aspartate transaminase (AS...
BMC Cancer
Background Saroglitazar is a novel PPAR-α/γ agonist with predominant PPAR-α activity. In various ... more Background Saroglitazar is a novel PPAR-α/γ agonist with predominant PPAR-α activity. In various preclinical models, saroglitazar has been shown to prevent & reverse symptoms of NASH. In view of these observations, and the fact that NASH is a progressive disease leading to HCC, we hypothesized that saroglitazar may prevent the development of HCC in rodents. Methods HCC was induced in C57BL/6 mice by a single intraperitoneal injection of 25 mg/kg diethylnitrosamine (DEN) at the age of 4 weeks and then feeding the animal a choline-deficient, L-amino acid- defined, high-fat diet (CDAHFD) for the entire study duration. Eight weeks after initiation of CDAHFD, saroglitazar (1 and 3 mg/kg) treatment was started and continued for another 27 weeks. Results Saroglitazar treatment significantly reduced the liver injury markers (serum ALT and AST), reversed hepatic steatosis and decreased the levels of pro-inflammatory cytokines like TNF-α in liver. It also resulted in a marked increase in seru...
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.
Vaccines remain the key protective measure to achieve herd immunity to control the disease burden... more Vaccines remain the key protective measure to achieve herd immunity to control the disease burden and stop COVID-19 pandemic. We have developed and assessed the immunogenicity and protective efficacy of two formulations (1mg and 2mg) of ZyCoV-D (a plasmid DNA based vaccine candidates) administered through Needle Free Injection System (NFIS) and syringe-needle (intradermal) in rhesus macaques with three dose vaccine regimens. The vaccine candidate 2mg dose administered using Needle Free Injection System (NFIS) elicited a significant immune response with development of SARS-CoV-2 S1 spike region specific IgG and neutralizing antibody (NAb) titers during the immunization phase and significant enhancement in the levels after the virus challenge. In 2 mg NFIS group the IgG and NAb titers were maintained and showed gradual rise during the immunization period (15 weeks) and till 2 weeks after the virus challenge. It also conferred better protection to macaques evident by the viral clearanc...
Bioorganic & Medicinal Chemistry
Scientific Reports
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...
Bioorganic & medicinal chemistry letters, 2018
TGR5 is a member of G protein-coupled receptor (GPCR) superfamily, a promising molecular target f... more TGR5 is a member of G protein-coupled receptor (GPCR) superfamily, a promising molecular target for metabolic diseases. Activation of TGR5 promotes secretion of glucagon-like peptide-1 (GLP-1), which activates insulin secretion. A series of 2-thio-imidazole derivatives have been identified as novel, potent and orally efficacious TGR5 agonists. Compound 4d, a novel TGR5 agonist, in combination with Sitagliptin, a DPP-4 inhibitor, has demonstrated an adequate GLP-1 secretion and glucose lowering effect in animal models, suggesting a potential clinical option in treatment of type-2 diabetes.
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
of compound 5 is depicted in Scheme 1a. The reductive amination 1 of commercially available 3-thi... more of compound 5 is depicted in Scheme 1a. The reductive amination 1 of commercially available 3-thiophene-aldehyde (3) and isopropyl amine using sodium triacetoxyborohydride resulted in secondary amine intermediate 4. Compound 4 on further reductive amination under similar conditions with aldehyde intermediate, (S)-3-(4-((3-formylbenzyl)oxy)phenyl)hex-4-ynoic acid (8), afforded 2d in high yields. The aldehyde intermediate, 8 was obtained from (S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (6) as shown in Scheme 1b. Acid 6 was synthesized via 5-step reported procedure using commercially available 4-hydroxybenzaldehyde and Meldrum's acid. 2 Resolution of racemic acid 6 was accomplished via diastereomeric salt formation with (1S,2R)-1-amino-2-indanol followed by salt break with aqueous acid to furnish compound 6. Treatment of 6 with of 40% aqueous tetrabutylphosphonium hydroxide (n-Bu 4 POH) in THF, followed by addition of 3-formyl benzyl bromide (7), afforded aldehyde intermediate 8. Compound 2d was further converted to its corresponding calcium salt (5) in two-step sequence with excellent chemical purity. Scheme 1a. Synthesis of Compounds 2d and 5. Reagent and Conditions: (a) CH(CH 3) 2 NH 2 , NaB(OAc) 3 H, CH 3 COOH, dry THF, 0 ᵒC to r.t., 16 h; (b) Comp 8, NaB(OAc) 3 H, CH 3 COOH, dry THF, 0 ᵒC to r.t., 16 h; (c) NaOH, MeCN/H 2 O, r.t., 3 h; (d) CaCl 2 , MeOH/H 2 O, r.t., 16 h. N-(thiophen-3-ylmethyl)propan-2-amine (4): To a stirred solution of thiophene-3-carbaldehyde (1.5 g, 13.37 mmol) in THF (10 mL), acetic acid (2.3 mL, 40.1 mmol) and solution of isopropylamine (2.3 mL, 26.7 mmol) in THF (5 mL) were added at 25 C and the reaction mixture was further stirred for 2 h at 25 C. After that sodium triacetoxyborohydride (7.09 g, 33.4 mmol) was added slowly at 25 C under nitrogen gas atmosphere. Resulted mixture was then stirred for 24 h at ambient temperature. Reaction was monitored by TLC (Reaction mixture + water + EtOAc, TLC was spotted from organic layer). Excess THF was removed under reduced pressure and the residue was acidified with dil. HCl. Aqueous layer was washed with EtOAc (50 mL x 3). Aqueous layer was collected and basified with 10% NaHCO 3 solution. Product was extracted with EtOAc (50 mL x 3). All organic layers were mixed together brine (25 mL). Organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure at (40C) to obtained, N-(thiophen-3-ylmethyl)propan-2-amine (2.0 g, 12.88 mmol, 96% yield) as Light yellow oil. % Yield = 96%.
ACS Medicinal Chemistry Letters, 2015
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/69147062/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.
ABSTRACTBackground and AimThe pathophysiology of NASH is complex owing to its diverse pathologica... more ABSTRACTBackground and AimThe pathophysiology of NASH is complex owing to its diverse pathological drivers, and until recently, there were no approved drugs for this disease.Tecomella undulatais a popular herbal medicine used to treat hepatosplenomegaly, hepatitis, and obesity. However, the potential role ofTecomella undulatain NASH has not yet been scientifically investigated.Experimental ProcedureMice fed with chow diet and normal water (CDNW) or western diet and sugar water (WDSW) for 12 weeks were randomized to receive vehicle control, Saroglitazar, orTecomella undulatafor an additional 12 weeks. Insulin resistance, lipid profiles, histological analysis, and liver enzymes were assessed. The oxidative stress, ER and inflammatory markers were determined by quantitative RT-PCR (qRT-PCR) and western blot analysis.Results and ConclusionThe administration ofTecomella undulatavia oral gavage lowered body weight, insulin resistance, alanine transaminase (ALT), aspartate transaminase (AS...
BMC Cancer
Background Saroglitazar is a novel PPAR-α/γ agonist with predominant PPAR-α activity. In various ... more Background Saroglitazar is a novel PPAR-α/γ agonist with predominant PPAR-α activity. In various preclinical models, saroglitazar has been shown to prevent & reverse symptoms of NASH. In view of these observations, and the fact that NASH is a progressive disease leading to HCC, we hypothesized that saroglitazar may prevent the development of HCC in rodents. Methods HCC was induced in C57BL/6 mice by a single intraperitoneal injection of 25 mg/kg diethylnitrosamine (DEN) at the age of 4 weeks and then feeding the animal a choline-deficient, L-amino acid- defined, high-fat diet (CDAHFD) for the entire study duration. Eight weeks after initiation of CDAHFD, saroglitazar (1 and 3 mg/kg) treatment was started and continued for another 27 weeks. Results Saroglitazar treatment significantly reduced the liver injury markers (serum ALT and AST), reversed hepatic steatosis and decreased the levels of pro-inflammatory cytokines like TNF-α in liver. It also resulted in a marked increase in seru...
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.
Vaccines remain the key protective measure to achieve herd immunity to control the disease burden... more Vaccines remain the key protective measure to achieve herd immunity to control the disease burden and stop COVID-19 pandemic. We have developed and assessed the immunogenicity and protective efficacy of two formulations (1mg and 2mg) of ZyCoV-D (a plasmid DNA based vaccine candidates) administered through Needle Free Injection System (NFIS) and syringe-needle (intradermal) in rhesus macaques with three dose vaccine regimens. The vaccine candidate 2mg dose administered using Needle Free Injection System (NFIS) elicited a significant immune response with development of SARS-CoV-2 S1 spike region specific IgG and neutralizing antibody (NAb) titers during the immunization phase and significant enhancement in the levels after the virus challenge. In 2 mg NFIS group the IgG and NAb titers were maintained and showed gradual rise during the immunization period (15 weeks) and till 2 weeks after the virus challenge. It also conferred better protection to macaques evident by the viral clearanc...
Bioorganic & Medicinal Chemistry
Scientific Reports
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...
Bioorganic & medicinal chemistry letters, 2018
TGR5 is a member of G protein-coupled receptor (GPCR) superfamily, a promising molecular target f... more TGR5 is a member of G protein-coupled receptor (GPCR) superfamily, a promising molecular target for metabolic diseases. Activation of TGR5 promotes secretion of glucagon-like peptide-1 (GLP-1), which activates insulin secretion. A series of 2-thio-imidazole derivatives have been identified as novel, potent and orally efficacious TGR5 agonists. Compound 4d, a novel TGR5 agonist, in combination with Sitagliptin, a DPP-4 inhibitor, has demonstrated an adequate GLP-1 secretion and glucose lowering effect in animal models, suggesting a potential clinical option in treatment of type-2 diabetes.
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
of compound 5 is depicted in Scheme 1a. The reductive amination 1 of commercially available 3-thi... more of compound 5 is depicted in Scheme 1a. The reductive amination 1 of commercially available 3-thiophene-aldehyde (3) and isopropyl amine using sodium triacetoxyborohydride resulted in secondary amine intermediate 4. Compound 4 on further reductive amination under similar conditions with aldehyde intermediate, (S)-3-(4-((3-formylbenzyl)oxy)phenyl)hex-4-ynoic acid (8), afforded 2d in high yields. The aldehyde intermediate, 8 was obtained from (S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (6) as shown in Scheme 1b. Acid 6 was synthesized via 5-step reported procedure using commercially available 4-hydroxybenzaldehyde and Meldrum's acid. 2 Resolution of racemic acid 6 was accomplished via diastereomeric salt formation with (1S,2R)-1-amino-2-indanol followed by salt break with aqueous acid to furnish compound 6. Treatment of 6 with of 40% aqueous tetrabutylphosphonium hydroxide (n-Bu 4 POH) in THF, followed by addition of 3-formyl benzyl bromide (7), afforded aldehyde intermediate 8. Compound 2d was further converted to its corresponding calcium salt (5) in two-step sequence with excellent chemical purity. Scheme 1a. Synthesis of Compounds 2d and 5. Reagent and Conditions: (a) CH(CH 3) 2 NH 2 , NaB(OAc) 3 H, CH 3 COOH, dry THF, 0 ᵒC to r.t., 16 h; (b) Comp 8, NaB(OAc) 3 H, CH 3 COOH, dry THF, 0 ᵒC to r.t., 16 h; (c) NaOH, MeCN/H 2 O, r.t., 3 h; (d) CaCl 2 , MeOH/H 2 O, r.t., 16 h. N-(thiophen-3-ylmethyl)propan-2-amine (4): To a stirred solution of thiophene-3-carbaldehyde (1.5 g, 13.37 mmol) in THF (10 mL), acetic acid (2.3 mL, 40.1 mmol) and solution of isopropylamine (2.3 mL, 26.7 mmol) in THF (5 mL) were added at 25 C and the reaction mixture was further stirred for 2 h at 25 C. After that sodium triacetoxyborohydride (7.09 g, 33.4 mmol) was added slowly at 25 C under nitrogen gas atmosphere. Resulted mixture was then stirred for 24 h at ambient temperature. Reaction was monitored by TLC (Reaction mixture + water + EtOAc, TLC was spotted from organic layer). Excess THF was removed under reduced pressure and the residue was acidified with dil. HCl. Aqueous layer was washed with EtOAc (50 mL x 3). Aqueous layer was collected and basified with 10% NaHCO 3 solution. Product was extracted with EtOAc (50 mL x 3). All organic layers were mixed together brine (25 mL). Organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure at (40C) to obtained, N-(thiophen-3-ylmethyl)propan-2-amine (2.0 g, 12.88 mmol, 96% yield) as Light yellow oil. % Yield = 96%.
ACS Medicinal Chemistry Letters, 2015
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.