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Synthesis and Caco-2 cell permeability of N-substituted anthranilamide esters as ADP inhibitor in platelets

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Abstract

Twelve N-substituted anthranilamide esters (1–5, 8, 9, 12, 13, and 15–17) were synthesized and evaluated for their ability to inhibit the in vitro aggregation by washed human platelets induced by adenosine 5′-diphosphate (10 μM). The antiplatelet activity of dl-n-butyl 5-hydroxy-N-(2-phenoxypropionyl)anthranilate (9, IC50 = 10.5 μM) was most active among the tested compounds and ethyl ester 8 (IC50 = 11.2 μM) showed the second most activity. dl-Ethyl and dl-n-butyl 5-(p-toluenesulfonyloxy)-N-(2-phenoxypropionyl)anthranilate (12, IC50 = 13.1 μM and 13, IC50 = 14.0 μM), dl-methyl N-(2-phenoxybutyryl)anthranilate (2, IC50 = 12.7 μM), dl-N-(2-phenoxypropionyl)anthranilic acid (5, IC50 = 13.7 μM) displayed lower antiplatelet activity than 8 and 9. Compound 5 was more active than methyl ester prodrug 1. n-Butyl 5-hydroxy-N-(4′-acetoxybenzoyl)anthranilate (15, IC50 = 28.3 μM) showed moderate activity. Compounds 1 (IC50 = 42.8 μM), 4 (IC50 = 56.7 μM), 16 (IC50 = 51.0 μM), and 17 (IC50 = 49.8 μM) exhibited low antiplatelet activity. Methyl N-phenoxyacetylanthranilate (3, IC50 = 78.0 μM) showed the lowest antiplatelet activity. The compounds with branched alkyl chain (2 and 5) were more active than compounds with straight chain (3 and 4). The apparent permeability coefficient (Papp, cm/s) values of compounds 2 and 9 were determined as 45.34 ± 4.67 and 33.17 ± 5.15 × 10−6 cm/s by Caco-2 cell permeability assay.

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References

  • Angiolillo, D.J., D.L. Bhatt, P.A. Gurbel, and L.A. Jennings. 2009. Advances in antiplatelet therapy: Agents in clinical development. American Journal of Cardiology 103: 40A–51A.

    Article  CAS  PubMed  Google Scholar 

  • Anninos, H., G. Andrikopoulos, S. Pastromas, D. Sakellarich, G. Theodorakis, and P. Vardas. 2009. Triflusal: An old drug in modern antiplatelet therapy. Review of its action, use, safety and effectiveness. Hellenic Journal of Cardiology 50: 199–207.

    PubMed  Google Scholar 

  • Antithrombotic triallist’s collaboration. 2002. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324: 71–86.

    Article  Google Scholar 

  • Artursson, P., and J. Karlsson. 1991. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochemical and Biophysical Research Communication 175: 880–885.

    Article  CAS  Google Scholar 

  • Artursson, P., K. Palm, and K. Luthman. 1996. Caco-2 monolayers in experimental and theoretical predictions of drug transport. Advanced Drug Delivery Reviews 22: 67–84.

    Article  CAS  Google Scholar 

  • Bennett, J.S. 2001. Novel platelet inhibitors. Annual Review of Medicine 52: 161–184.

    Article  CAS  PubMed  Google Scholar 

  • Berger, P.B. 1999. The thienopyridines in coronary artery disease. Current Cardiology Reports 1: 192–198.

    Article  CAS  PubMed  Google Scholar 

  • Bhatt, D.L., and E.J. Topol. 2003. Scientific and therapeutic advances in antiplatelet therapy. Nature Reviews Drug Discovery 2: 15–28.

    Article  CAS  PubMed  Google Scholar 

  • Born, G.V.R. 1962. Aggregation of blood platelets by adenosine diphosphate (ADP) and its reversal. Nature 194: 927–929.

    Article  CAS  PubMed  Google Scholar 

  • Borne, R.F., R.L. Peden, I.W. Waters, M. Weiner, R. Jordan, and E.A. Coats. 1974. Anti-inflammatory activity of para-substituted N-benzenesulfonyl derivatives of anthranilic acid. Journal of Pharmaceutical Sciences 63: 615–617.

    Article  CAS  PubMed  Google Scholar 

  • Caldwell, G.W., D.M. Richie, and J.A. Masucci. 2001. The new pre-preclinical paradigm: Compound optimization in early and late phase drug discovery. Current Topics in Medicinal Chemistry 1: 353–366.

    Article  CAS  PubMed  Google Scholar 

  • Daniel, J.L., C. Dangelmaier, J. Jin, B. Ashby, J.B. Smith, and S.P. Kunapuli. 1998. Molecular basis for ADP induced platelet activation, I: Evidence for three distinct ADP receptors on human platelets. Journal of Biological Chemistry 273: 2024–2029.

    Article  CAS  PubMed  Google Scholar 

  • Davi, G., and C. PatRono. 2007. Platelet activation and atherothrombosis. New England Journal of Medicine 357: 2482–2494.

    Article  CAS  PubMed  Google Scholar 

  • Eisert, W.G. 2001. How to get from antiplatelet to antithrombotic treatment. American Journal of Therapeutics 8: 443–449.

    Article  CAS  PubMed  Google Scholar 

  • Gan, L.-S., and D. Thakker. 1997. Applications of the Caco-2 model in the design and development of orally active drug elucidation of biochemical and physical barriers posed by the intestinal epithelium. Advanced Drug Delivery Reviews 23: 77–98.

    Article  CAS  Google Scholar 

  • He, X., M. Sugawara, Y. Takekuma, and K. Hiyazaki. 2004. Absorption of ester prodrugs in Caco-2 and rat intestine models. Antimicrobial Agents and Chemotherapy 48: 2604–2609.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ha-Duong, N.T., S. Dijols, A.-C. Macherey, J.A. Goldstein, P.M. Dansette, and D. Mansey. 2001. Ticlopidine as a selective mechanism-based inhibitor of human cytochrome P450 2C19. Biochemistry 40: 12112–12122.

    Article  CAS  PubMed  Google Scholar 

  • Ho, P.M., T.M. Maddox, L. Wang, S.D. Fihn, R.L. Jesse, E.D. Peterson, and J.S. Rumsfeld. 2009. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. Journal of the American Medical Association 301: 937–944.

    Article  CAS  PubMed  Google Scholar 

  • Hsieh, P.W., S.Z. Chiang, C.C. Wu, Y.C. Lo, Y.T. Shih, and Y.C. Wu. 2008. Synthesis and anti-platelet evaluation of 2-benzoylaminobenzoate analogs. Bioorganic & Medicinal Chemistry 16: 5803–5814.

    Article  CAS  Google Scholar 

  • Hsieh, P.W., T.L. Hwang, C.C. Wu, S.Z. Chiang, C.L. Wu, and Y.C. Wu. 2007. The evaluation and structure-activity relationships of 2-benzoylaminobenzoic esters and their analogues as anti-inflammatory and anti-platelet aggregation agents. Bioorganic & Medicinal Chemistry Letters 17: 1812–1817.

    Article  CAS  Google Scholar 

  • Iwasa, Y., T. Iwasa, K. Matsui, T. Yoshimura, N. Tanaka, and K. Miyazaki. 1986. Anti-platelet action of an anti-allergic agent, N-(3′,4′-dimethoxycinnamoyl)anthranilic acid (Tranilast). European Journal of Pharmacology 120: 231–234.

    Article  CAS  PubMed  Google Scholar 

  • Jackson, S.P., and S.M. Schoenwaelder. 2003. Antiplatelet therapy in search of the ‘magic bullet’. Nature Reviews Drug Discovery 2: 775–789.

    Article  CAS  PubMed  Google Scholar 

  • Kunapuli, S.D. 1998. Multiple P2 receptor subtypes on platelets: A new interpretation of their function. Trends in Pharmacological Sciences 19: 391–394.

    Article  CAS  PubMed  Google Scholar 

  • Lim, J.K., W.S. Woo, K.R. Lee, and E. Ma. 1994. Synthesis of melandrin derivatives. Yakhak Hoeji 38: 281–285.

    CAS  Google Scholar 

  • Liu, F.-C., C.-H. Liao, Y.-E. Chang, J.-T. Liou, and Y.-J. Day. 2009. A new insight of anti-platelet effects of sirtinol in platelets aggregation via cyclic AMP phosphodiesterse. Biochemical Pharmacology 77: 1364–1373.

    Article  CAS  PubMed  Google Scholar 

  • Losena, M.V., and B.M. Bolotin. 1972. Reaction of anthranilic acid and methoxy- and nitro-substituted anthranilic acid with p-toluenesulfonyl chloride in pyridine. Chemistry of Heterocyclic Compounds 8: 1212–1215.

    Article  Google Scholar 

  • Maekowska, M., S. Oberle, C.-P. Juzwin, M. Hsu, M. Gryszkiewicz, and A.J. Streeter. 2001. Optimizing Caco-2 cell monolayers to increase throughput in drug intestinal absorption analysis. Journal of Pharmacological and Toxicological Methods 46: 51–55.

    Article  Google Scholar 

  • Manikeri, S.R., C.N. Raghu, V.N. Dadlkar, and U.K. Sheth. 1980. Effect of Tromaril on platelet and blood coagulation. Indian Journal of Medical Research 71: 438–445.

    CAS  PubMed  Google Scholar 

  • Michelson, A.D. 2010. Antiplatelet therapies for the treatment of cardiovascular disease. Nature Reviews Drug Discovery 9: 154–169.

    Article  CAS  PubMed  Google Scholar 

  • Schrör, K. 1995. Antiplatelet drugs: A comparative reviews. Drugs 50: 7–28.

    Article  PubMed  Google Scholar 

  • Turner, N.A., J.L. Moake, and L.V. McIntire. 2001. Blockade of adenosine diphosphate receptors P2Y(12) and P2Y(1) is required to inhibit platelet aggregation in whole blood under flow. Blood 98: 3340–3345.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0013516).

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  1. College of Pharmacy, Catholic University of Daegu, 712-702, Hayangro 13-13, Gyeongsan, 712-702, Korea

    Sohee Kim, Beom Soo Shin & Eunsook Ma

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  1. Sohee Kim
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Correspondence to Eunsook Ma.

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Kim, S., Shin, B.S. & Ma, E. Synthesis and Caco-2 cell permeability of N-substituted anthranilamide esters as ADP inhibitor in platelets. Arch. Pharm. Res. 38, 1147–1156 (2015). https://doi.org/10.1007/s12272-014-0353-1

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