Therapeutics

Knowledge-base on diabetes/dyslipidemia and metabolic syndrome through basic research.

Improving Insulin sensitivity/ glucose tolerance

Improvement of circulating lipid profile

Anti-diabetic/dyslipidemic molecules by target based drug designs and synthesis:

Targets:

                GLP-1 analog

                DPPIV inhibitor

Natural product as a source of biologically active Anti-diabetic/dyslipidemic molecules (marine/terrestrial).

In vitro cell based screening.

• Glucose-uptake assays in L6 Muscle cells

• 3T3L-1 –based assays on adipocyte differentiation

• Hepatocyte based screenings on cholesterol and glucose metabolism

In vivo screening
 

 Diabetes:

§  Streptozotocin-induced diabetic mice

§  Sucrose loading model

§  db/db mice. Dyslipidemia: High fat fed Syrian hamsters.

 Dyslipidemia

§   High fat fed Syrian hamsters

Studies on functional regulation of carbohydrate and lipid metabolism by metabolic nuclear receptors.

Proteomic analysis of 3T3L-1 cells treated with adipogenic compounds

Studies on pancreatic ER stress.

CDR-134D123 (anti-hyperglycemic, Phase I): Natural product

CDR134F194: IND filed

Puffer fish oil: IND filed.

8 lead compounds identified with anti-hyperglycemic and/oranti-dyslipidemic activities

    Development and optimization of proteomic approaches for proteomic profiling of lead compound treated
target tissues.

Development and optimization of screening systems for metabolic nuclear receptors

Khan MP, Singh AK, Joharapurkar AA, Yadav M, Shree S, Kumar H, Gurjar A, Mishra JS, Chandra Tiwari M, Nagar GK, Kumar S, Ramachandran R, Sharan A, Jain MR, Trivedi AK, Maurya R, Godbole MM, Gayen JR, Sanyal S, Chattopadhyay N. (2015) Pathophysiological mechanism of bone loss in type 2 diabetes involves inverse regulation of osteoblast function by PPARγ coactivator-1α and skeletal muscle atrogenes: adiponectin receptor 1 as a potential target for reversing diabetes-induced osteopenia. Diabetes. 64(7):2609-23

Singh AK, Joharapurkar AA, Khan MP, Mishra JS, Singh N, Yadav M, Hossain Z, Khan K, Kumar S, Dhanesha NA, Mishra DP, Maurya R, Sharma S, Jain MR, Trivedi AK, Godbole MM, Gayen JR, Chattopadhyay N, Sanyal S.(2014). Orally active osteoanabolic agent GTDF binds to adiponectin receptors, with a preference for AdipoR1, induces adiponectin-associated signaling, and improves metabolic health in a rodent model of diabetes. Diabetes. 63(10):3530-44.

Bandyopadhyay GK, Lu M, Avolio E, Siddiqui JA, Gayen JR, Wollam J, Vu CU, Chi NW, O'Connor DT, Mahata SK. (2015) Pancreastatin-dependent inflammatory signaling mediates obesity-induced insulin resistance.Diabetes, 64(1):104-16.

. Jaiswal N, Maurya CK, Arha D, Avisetti DR, Prathapan A, Raj PS, Raghu KG, Kalivendi SV, Tamrakar AK. (2015) Fructose induces mitochondrial dysfunction and triggers apoptosis in skeletal muscle cells by provoking oxidative stress. Apoptosis. 20(7):930-47.

Verma S, Arha D, Tamrakar AK, Srivastava SK. (2015) Glycolipids: isolated from Oplismenusburmannii induce glucose uptake in L6-GLUT4myc myotube cells. Curr Top Med Chem. 15(11):1027-34.

Korthikunta V, Pandey J, Singh R, Srivastava R, Srivastava AK, Tamrakar AK, Tadigoppula N. (2015) In vitro anti-hyperglycemic activity of 4-hydroxyisoleucine derivatives.Phytomedicine. 22(1):66-70.

Rawat AK, Korthikunta V, Gautam S, Pal S, Tadigoppula N, Tamrakar AK, Srivastava AK. (2014) 4-Hydroxyisoleucine improves insulin resistance by promoting mitochondrial biogenesis and act through AMPK and Akt dependent pathway. Fitoterapia. 99:307-17.

Jaiswal N, Gunaganti N, Maurya CK, Narender T, Tamrakar AK. (2015). Free fatty acid induced impairment of insulin signaling is prevented by the diastereomeric mixture of calophyllic acid and isocalophyllic acid in skeletal muscle cells. Eur J Pharmacol. 746:70-7.

Riya MP, Antu KA, Pal S, Chandrakanth KC, Anilkumar KS, Tamrakar AK, Srivastava AK, Raghu KG. (2015). Antidiabetic property of Aervalanata (L.) Juss. exSchult. is mediated by inhibition of alpha glucosidase, protein glycation and stimulation of adipogenesis. J Diabetes. 7(4):548-61

Antidiabetic property of Symplocoscochinchinensis is mediated by inhibition of alpha glucosidase and enhanced insulin sensitivity. (2014). Antu KA, Riya MP, Mishra A, Anilkumar KS, Chandrakanth CK, Tamrakar AK, Srivastava AK, Raghu KG. PLoS One. 2014 Sep 3;9(9):e105829.

Sharma DK, Pandey J, Tamrakar AK, Mukherjee D. (2014). Synthesis of heteroaryl/aryl kojic acid conjugates as stimulators of glucose uptake by GLUT4 translocation. Eur J Med Chem.;85:727-36.

Tamrakar AK, Maurya CK, Rai AK. (2014). PTP1B inhibitors for type 2 diabetes treatment: a patent review (2011 - 2014). Expert OpinTher Pat. 24(10):1101-15.

Maurya CK, Singh R, Jaiswal N, Venkateswarlu K, Narender T, Tamrakar AK.(2014). 4-Hydroxyisoleucine ameliorates fatty acid-induced insulin resistance and inflammatory response in skeletal muscle cells. Mol Cell Endocrinol. 395(1-2):51-60.

Khan MF, Maurya CK, Dev K, Arha D, Rai AK, Tamrakar AK, Maurya R. (2014). Design and synthesis of lupeol analogues and their glucose uptake stimulatory effect in L6 skeletal muscle cells. Bioorg Med ChemLett. 24(12):2674-9.

Pandey J, Maurya R, Raykhera R, Srivastava MN, Yadav PP, Tamrakar AK. (2014). Murrayakoenigii (L.) Spreng. ameliorates insulin resistance in dexamethasone-treated mice by enhancing peripheral insulin sensitivity. J Sci Food Agric. 94(11):2282-8.

Antihyperglycemic activity of phenylpropanoyl esters of catechol glycoside and its dimmers from Dodecadenia grandifloraManmeet Kumar, Preeti Rawat, Neha Rahuja, Arvind K.Srivastava, Rakesh MauryaPhytochemistry (In press)

Synthesis of novel triterpenoid (Lupeol) derivatives and their in-vivo antihyperglycemic and antidyslipidemic activity. K.Papi Reddy, AB Singh, A Puri, AK Srivastava, T. Narender Bioorg. Med. Chem. Letters (2009), 19(15):4463-6.

Synthesis of α- amyrin derivatives and their in vivo antihyperglycemic activity T Narender, T Khaliq, AB Singh, MD Joshi, P Mishra, JP Chaturvedi, AK Srivastava, R Maurya, SC Agarwal. European J. Med Chem. (2009), 44, 1215-1222

Structure and activities of a steroidal saponin from Chlorophytum nimonii (Grah) Dalz.Lakshmi V, Kumar R, Pandey K, Joshi BS, Roy R, Madhusudanan KP, Tiwari P, Srivastava AK. Natural Products Research. (2009) 23(10):963-72

Design and synthesis of 3, 5-diarylisoxazole derivatives as novel class of anti-hyperglycemic and lipid lowering agents. Kumar A, Maurya RA, Sharma S, Ahmad P, Singh AB, Tamrakar AK, Srivastava AK. Bioorg. Med..Chem.(2009), 17(14): 5285-5292

Synthetic studies in butenonyl C-glycosides: Preparation of polyfunctional alkanonyl glycosides and their enzyme inhibitory activity. Bisht SS, Fatima S, Tamrakar AK, Rahuja N, Jaiswal N, Srivastava AK, Tripathi RP. Bioorg. Med. Chem. Letters (2009) 19 (10):2699-703

5, 6-Diarylanthranilo-1,3-dinitriles as a new class of antihyperglycemic agents. Singh FV, Parihar A, Chaurasia S, Singh AB, Singh SP, Tamrakar AK, Srivastava AK, Goel A  Bioorg. Med. Chem. Letters. (2009) 19(8):2158-61

Synthesis of protein tyrosine phosphatase 1B inhibitors: model validation and docking studies. Saxena AK, Pandey G, Gupta S, Singh AB, Srivastava AK. Bioorg. Med. Chem. Letters. (2009) 19(8):2320-3

db/+ Mice as an alternate model in antidiabetic drug discovery research. Tamrakar AK, Singh AB, Srivastava AK. Arch Med. Res., (2009) 40 (2):73-8

Novel class of hybrid natural products as antidiabetic agents. Raj K, Misra N, Pachauri G, Sharma M, Tamrakar AK, Singh AB, Srivastava AK, Phani Kiran K, Narasimha Rao CV, Prabhu SR. Natural Products Research (2009) 23(1):60-9

Novel 2-aryl-naphtho[1,2-d]oxazole derivatives as potential PTP-1B inhibitors showing antihyperglycemic activities. Kumar A, Ahmad P, Maurya RA, Singh AB, Srivastava AK. European J. Med. Chem. (2009) 44 (1):109-16

Identification of pongamol and karanjin as lead compounds with antihyperglycemic activity from Pongamia pinnata fruits. Tamrakar AK, Yadav PP, Tiwari P, Maurya R, Srivastava AK. J  Ethnopharmacol. (2008) 118 (3):435-9

Antihyperglycemic activity of Sinularia firma and Sinularia erecta in streptozotocin-induced diabetic rats. Akhilesh K. Tamrakar, Priti Tiwari, Rehan Ahmad, Rajesh Kumar, Vijai Lakshmi, Mahendra Nath Srivastava, Arvind K. Srivastava Med. Chem. Res., (2008) 17:62-73

.Synthesis of 3,5-disubsituted isoxazolines as protein tyrosine phosphatase 1B inhibitors.Rakesh Maurya, Prasoon Gupta, Ghufran Ahmad, Dinesh Kumar Yadav, Kailash Chand, Amar Bahadur Singh, Akhilesh K. Tamrakar, Arvind K. Srivastava Med. Chem. Res. (2008) 17:123-136

Synthesis and antihyperglycemic activity of novel N-acyl-2-arylethylamines and N-acyl-3-coumarylamines. Dwivedi AP, Kumar S, Varshney V, Singh AB, Srivastava AK, Sahu DP. Bioorg. Med. Chem. Letters. (2008) 18(7):2301-5