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Trifluorophenyl-based inhibitors of dipeptidyl peptidase-IV as antidiabetic agents: 3D-QSAR COMFA, CoMSIA methodologies

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Abstract

3D-QSAR CoMFA and CoMSIA studies were performed on a set of trifluorophenyl derivatives as dipeptidyl peptidase IV inhibitors. Based on the results, predictive QSAR models were established, with cross-validated coefficient values (q 2) up to 0.879 for CoMFA. CoMSIA model developed using combination of steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor features has shown q 2 (cross-validated) 0.875. These developed models may be useful in the identification and optimization of novel scaffolds with potent dipeptidyl peptidase IV activity.

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References

  • Abel T, Feher J (2010) A new therapeutic possibility for type 2 diabetes: DPP-4 inhibitors (Sitagliptin). Orvsi Hetil 151:1012–1016

    Article  Google Scholar 

  • Ahn JH, Park WS, Jun MA, Shin MS, Kang SK, Kim KY, Rhee SD, Bae MA, Kim KR, Kim SG, Kim SY, Sohn SK, Kang NS, Lee JO, Lee DH, Cheon HG, Kim SS (2008) Synthesis and biological evaluation of homopiperazine derivatives with beta-aminoacyl group as dipeptidyl peptidase IV inhibitors. Bioorg Med Chem Lett 18:6525–6529

    Article  Google Scholar 

  • Augeri DJ, Robl JA, Betebenner DA, Magnin DR, Khanna A, Robertson JG, Wang A, Simpkins LM, Taunk P, Huang Q, Han SP, Abboa-Offei B, Cap M, Xin L, Tao L, Tozzo E, Welzel GE, Egan DM, Marcinkeviciene J, Chang SY, Biller SA, Kirby MS, Parker RA, Hamann LG (2005) Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 48:5025–5037

    Article  Google Scholar 

  • Barnett A (2007) Exenatide. Exp Opin Pharmacother 8:2593–2608

    Article  Google Scholar 

  • Bush BL, Nachbar RB Jr (1993) Sample-distance partial least squares: PLS optimized for many variables, with application to CoMFA. J Comput Aided Mol Des 7:587–619

    Article  Google Scholar 

  • Cramer RD, Patterson DE, Bunce JD (1988) Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110(18):5959–5967

    Article  Google Scholar 

  • Deacon CF, Holst JJ, Carr RD (1999) Glucagon-like peptide-1: a basis for new approaches to the management of diabetes. Drugs Today (Barc) 35:159–170

    Article  Google Scholar 

  • Drab SR (2009) Clinical studies of Liraglutide, a novel, once-daily human glucagon-like peptide-1 analog for improved management of type 2 diabetes mellitus. Pharmacotherapy 29:43S–54S

    Article  Google Scholar 

  • Farilla L (2002) Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology 143(11):4397–4408

    Article  Google Scholar 

  • Feng J, Zhang Z, Wallace MB, Stafford JA, Kaldor SW, Kassel DB, Navre M, Shi L, Skene RJ, Asakawa T, Takeuchi K, Xu R, Webb DR, Gwaltney SL 2nd (2007) Discovery of Alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J Med Chem 50:2297–2300

    Article  Google Scholar 

  • Gallwitz B (2010) Diabetes therapy novel drugs to come (DPP-4 inhibitors, GLP-1 agonists, SGLT-2 inhibitors). MMW Fortschr Med 152:43–44

    Article  Google Scholar 

  • Gao Y-D, Feng D, Sheridan RP et al (2007) Modeling assisted rational design of novel, potent, and selective pyrrolopyrimidine DPP-4 inhibitors. Bioorg Med Chem Lett 17(14):3877–3879

    Article  Google Scholar 

  • He YL, Horowitz A, Watson CE, Foley JE, Sallas W, Ligueros-Saylan M (2007) Vildagliptin does not affect C-peptide clearance in patients with type 2 diabetes. J Clin Pharmacol 47:127–131

    Article  Google Scholar 

  • Herman GA, Stein PP, Thornberry NA, Wagner JA (2007) Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: focus on Sitagliptin. Clin Pharmacol Ther 81:761–767

    Article  Google Scholar 

  • Hollander PA, Kushner P (2010) Type 2 diabetes comorbidities and treatment challenges: rationale for DPP-4 inhibitors. Postgrad Med 122:71–80

    Article  Google Scholar 

  • Janardhan S, Padmanabha Reddy Y (2011) Molecular modeling studies of β-aminoacyl containing homopiperazine derivatives as DPP 4 inhibitors. Int J Drug Des Discov 2(3):533–547

    Google Scholar 

  • Jiang Y-K (2010) Molecular docking and 3D-QSAR studies on β-phenylalanine derivatives as dipeptidyl peptidase IV inhibitors. J Mol Model 16(7):1239–1249

    Article  Google Scholar 

  • Jun MA, Park WS, Kang SK, Kim KY, Kim KR, Rhee SD, Bae MA, Kang NS, Sohn SK, Kim SG, Lee JO, Lee DH, Cheon HG, Kim SS, Ahn JH (2008) Synthesis and biological evaluation of pyrazoline analogues with beta-amino acyl group as dipeptidyl peptidase IV inhibitors. Eur J Med Chem 43:1889–1902

    Article  Google Scholar 

  • Kim D, Wang L, Beconi M, Eiermann GJ, Fisher MH, He H, Hickey GJ, Kowalchick JE, Leiting B, Lyons K, Marsilio F, McCann ME, Patel RA, Petrov A, Scapin G, Patel SB, Roy RS, Wu JK, Wyvratt MJ, Zhang BB, Zhu L, Thornberry NA, Weber AE (2005) (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 48:141–151

    Article  Google Scholar 

  • Kim D, Kowalchick JE, Brockunier LL, Parmee ER, Eiermann GJ, Fisher MH, He H, Leiting B, Lyons K, Scapin G, Patel SB, Petrov A, Pryor KD, Roy RS, Wu JK, Zhang X, Wyvratt MJ, Zhang BB, Zhu L, Thornberry NA, Weber AE (2008) Discovery of potent and selective dipeptidyl peptidase IV inhibitors derived from beta-aminoamides bearing substituted triazolopiperazines. J Med Chem 51:589–602

    Article  Google Scholar 

  • Klebe G, Abraham U, Mietzner T (1994) Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity. J Med Chem 37:4130–4146

    Article  Google Scholar 

  • Kovalishyn V, Tanchuk V, Charochkina L et al (2012) Predictive QSAR modeling of phosphodiesterase 4 inhibitors. J Mol Graph Model 32:32–38

    Article  Google Scholar 

  • Migoya EM, Bergeron R, Miller JL, Snyder RN, Tanen M, Hilliard D, Weiss B, Larson P, Gutierrez M, Jiang G, Liu F, Pryor KA, Yao J, Zhu L, Holst JJ, Deacon C, Herman G, Thornberry N, Amatruda J, Williams-Herman D, Wagner JA, SinhaRoy R (2010) Dipeptidyl peptidase-4 inhibitors administered in combination with metformin result in an additive increase in the plasma concentration of active GLP-1. Clin Pharmacol Ther 88:801–808

    Article  Google Scholar 

  • Nordhoff S, López-Canet M, Hoffmann-Enger B, Bulat S, Cerezo-Gálvez S, Hill O, Rosenbaum C, Rummey C, Thiemann M, Matassa VG, Edwards PJ, Feurer A (2009) From lead to preclinical candidate optimization of beta-homophenylalanine based inhibitors of dipeptidyl peptidase IV. Bioorg Med Chem Lett 19:4818–4823

    Article  Google Scholar 

  • Park WS, Jun MA, Shin MS, Kwon SW, Kang SK, Kim KY, Dal Rhee S, Bae MA, Narsaiah B, Lee DH, Cheon HG, Ahn JH, Kim SS (2009) Synthesis and biological evaluation of triazepane derivatives as DPP-IV inhibitors. J Fluor Chem 130:1001–1010

    Article  Google Scholar 

  • Peters JU, Weber S, Kritter S, Weiss P, Wallier A, Boehringer M, Hennig M, Kuhn B, Loeffler BM (2004) Aminomethylpyrimidines as novel DPP-IV inhibitors: a 10(5)-fold activity increase by optimization of aromatic substituents. Bioorg Med Chem Lett 14:1491–1493

    Article  Google Scholar 

  • Pissurlenkar RRS, Shaikh MS, Coutinho EC (2007) 3D-QSAR studies of dipeptidyl peptidase IV inhibitors using a docking based alignment. J Mol Model 13(10):1047–1071

    Article  Google Scholar 

  • Villhauer EB, Brinkman JA, Naderi GB, Dunning BE, Mangold BL, Mone MD, Russell ME, Weldon SC, Hughes TE (2002) 1-[2-[(5-Cyanopyridine-2-yl)amino]ethylamino]acetyl-2-(S)-pyrrolidinecarbonitrile: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem 45:2362–2365

    Article  Google Scholar 

  • Viswanadhan VN, Ghose AK, Revankar RG, Robins RK (1989) Atomic physicochemical parameters for three dimensional structure directed quantitative structure–activity relationships. 4. Additional parameters for hydrophobic and dispersive interactions and their application for an automated superposition of certain naturally occurring nucleoside antibiotics. J Chem Inf Comput Sci 29(3):163–172

    Article  Google Scholar 

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Acknowledgements

The authors are thankful to Head, School of Pharmacy, DAVV Indore for providing necessary facilities. S. Jain thanks the All India Council for Technical Education (AICTE), New Delhi, India, for the financial support for this research.

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  1. School of Pharmacy, Devi Ahilya Vishwavidyalaya, Indore, Madhya Pradesh, 452001, India

    M. C. Sharma, S. Jain & R. Sharma

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  1. M. C. Sharma
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  2. S. Jain
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  3. R. Sharma
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Correspondence to S. Jain.

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Sharma, M.C., Jain, S. & Sharma, R. Trifluorophenyl-based inhibitors of dipeptidyl peptidase-IV as antidiabetic agents: 3D-QSAR COMFA, CoMSIA methodologies. Netw Model Anal Health Inform Bioinforma 7, 1 (2018). https://doi.org/10.1007/s13721-017-0163-8

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