Synthesis and Biological Evaluation of 3-(4-aminophenyl)-2-(1H-indol-3-yl) Propanamide derivatives as novel PTP1B Inhibitors

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Synthesis and Biological Evaluation of 3-(4-aminophenyl)-2-(1H-indol-3-yl) Propanamide derivatives as novel PTP1B Inhibitors

Author Affiliations

¹Medicinal Chemistry, Aurigene Discovery Technologies Ltd, Hosur Road, Bangalore – 560100, INDIA
²Department of Chemistry, JNTUH College of Engineering, Hyderabad - 500085, INDIA

Res.J.chem.sci., Volume 2, Issue (9), Pages 63-71, September,18 (2012)

Abstract

Indole scaffold represents one of the most important subunit explored in medicinal chemistry. We explored the possibilities of using the 3-(4-aminophenyl)-2-(1H-indol-3-yl)propanamide derivatives as PTP1B inhibitors. These inhibitors were designed based on molecular docking studies. Among the prioritized molecule 2-((4-(3-amino-2-(1H-indol-3-yl)-3-oxopropyl) phenyl) amino)-2-oxoacetic acid and their derivatives found to show reasonable potency for PTP1B. These compounds were examined for PTP1B inhibition through in-vitro assay. Best compound 15a showed Ki of 52 µM.

References

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[ref1] Andres Alonso, Joanna Sasin, Nunzio Bottini, Ilan Friedberg, Iddo Friedberg, Andrei Osterman, Adam Godzik, Tony Hunter, Jack Dixon and Tomas Mustelin,Protein Tyrosine Phosphatases in the Human Genome., Cell.,117, 699-711 (2004)

[ref2] Katherine R. Schiller and Laura J. Mauro, Tyrosine phosphatases as regulators of skeletal development and metabolism, J. Cell Biochem. 96, 262-277 (2005)

[ref3] Tony Hunter, Signaling—2000 and BeyondCell, 100, 113-127 (2000)

[ref4] Jacqueline Montalibet and Brian P. Kennedy, Therapeutic strategies for targeting PTP1B in diabetes, Drug Discovery TodayTherap. Strateg.,2, 129-135 (2005)

[ref5] Mounib Elchebly, Paul Payette, Eva Michaliszyn, WandaCromlish, Susan Collins, Ailsa Lee Loy, Denis Normandin, Alan Cheng, Jean Himms-Hagen, Chi-Chung Chan, Chidambaram Ramachandran, Michael J. Gresser, Michel L. Tremblay, and Brian P. Kennedy.,Increased Insulin Sensitivity and Obesity Resistance in Mice Lacking the Protein Tyrosine Phosphatase-1B Gene.,Science.,283, 1544-1548 (1999)

[ref6] Lori D. Klaman, Olivier Boss, Odile D. Peroni, Jason K. Kim, Jennifer L. Martino, Janice M. Zabolotny, Nadeem Moghal, Margaret Lubkin, Young-Bum Kim, Arlene H. Sharpe, Alain Stricker-Krongrad, Gerald I. Shulman, Benjamin G. Neel, and Barbara B. Kahn., Energy Expenditure, Decreased Adiposity, and Tissue Specific Insulin Sensitivity in Protein Phosphatase 1B-Deficient Mice., Mol. Cell Biol 5489 (2000)

[ref7] Gang Liu, Zhili Xin, Heng Liang, Cele Abad Philip J. Hajduk, David A. Janowick, Bruce G. Szczepankiewicz, Zhonghua Pei, Charles W. Hutchins, Stephen J. Ballaron, Michael A. Stashko,Thomas H. Lubben, Cathy E. Berg, Cristina M. Rondinone, James M. Trevillyan, and Michael R. Jirousek., Tyrosine Phosphatase 1B Inhibitors: Targeting the Second Phosphotyrosine Binding Site with Non Containing Ligands., J. Med. Chem. (2003)

[ref8] Zhili Xin, Gang Liu, Cele Abad-Zapatero, Zhonghua Pei, Bruce G. Szczepankiewicz, Xiaofeng Li, Tianyuan Zhang, Charles W. Hutchins,Philip J. Hajduk, Stephen J. Ballaron, Michael A. Stashko, Thomas H. Lubben,James M Trevillyana and Michael R. Jirousek.., monoacid-Based, cell permeable, selective inhibitor of 13, 3947–3950 (2003)

[ref9] Matthew E. Welsch, Scott A Stockwell., Privileged Scaffolds for Library Design and Drug Discovery., Curr Opin Chem Biol. (2010)

[ref10] Fernando Rodrigues de Sa Alves Carlos Alberto Manssour Fraga. Discovery: The Indole Scaffold as a 'Privileged Structure Mini Reviews in Medicinal Chemistry;9(7), 782-793 (2009)

[ref11] Prajapati Ajaypal., Synthesis, Antimicrobial and Insecticidal Activity Studies of 5 2-(Substituted Aryl)-3- Oxothiazolidines., Research , 99-104 (2012)

[ref12] Douglas P. Wilson, Zhao-Kui Wan, Wei Kirincich, Bruce C. Follows, Diane Joseph Kenneth Foreman, Alessandro Moretto, Junjun Wu, Min Zhu, Eva Binnun, Yan-Ling Zhang,| May Tam, David V. Erbe, James Tobin, Xin Xu, Louis Leung, Adam Shilling, Steve Y. Tam, Tarek S. Mansour, and Jinbo Lee.; Structure-Based Optimization of Protein TyrSecond Phosphotyrosine Binding Site.,J. Med. Chem., 50, 4681 (2007)

[ref13] M.V.V.V.Sekhar Reddy, G.Chakshusmathi, P.C.Arun, M. Lakshmi Narasu.; Developing select PTP1B over TCPTP., Journal of Global Trends in Pharmaceutical Sciences, 3(1), 558-563, (2012)