Peripherally Restricted, Highly Potent, Selective, Aqueous-Soluble EP2 Antagonist with Anti-Inflammatory Properties.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 101197791 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1543-8392 (Electronic) Linking ISSN: 15438384 NLM ISO Abbreviation: Mol Pharm Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : American Chemical Society, c2004-
    • Subject Terms:
    • Abstract:
      The prostaglandin E 2 receptor, EP2, plays an important role in physiology and in a variety of pathological conditions. Studies indicate that EP2 is pro-inflammatory in chronic peripheral and central nervous system disease and cancer models. Thus, targeting the EP2 receptor with small molecules could be a therapeutic strategy for treating inflammatory diseases and cancer. We recently reported a novel class of competitive antagonists of the EP2 receptor. However, earlier leads displayed low selectivity against the DP1 prostanoid receptor, moderate plasma half-life, and low aqueous solubility, which renders them suboptimal for testing in animal models of disease. We now report a novel compound TG8-69, which has suitable drug-like properties. We present synthesis, lead-optimization studies, pharmacological characterization, and anti-inflammatory properties of this compound that support its use in chronic peripheral inflammatory diseases, including rheumatoid arthritis, endometriosis, and cancer, in which EP2 appears to play a pathogenic role.
    • References:
      Anal Chem. 2000 Apr 15;72(8):1781-7. (PMID: 10784141)
      Am J Physiol Regul Integr Comp Physiol. 2000 Jun;278(6):R1415-23. (PMID: 10848506)
      Ann N Y Acad Sci. 2000;919:26-32. (PMID: 11083094)
      Arthritis Rheum. 2000 Dec;43(12):2687-93. (PMID: 11145026)
      J Clin Invest. 2002 Sep;110(5):651-8. (PMID: 12208866)
      Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):9044-9. (PMID: 12835414)
      Arthritis Rheum. 2004 Jun;50(6):1774-80. (PMID: 15188353)
      Science. 2004 Dec 10;306(5703):1954-7. (PMID: 15550624)
      Oncogene. 2006 Sep 7;25(40):5507-16. (PMID: 16607275)
      Lab Invest. 2007 Jan;87(1):49-55. (PMID: 17075575)
      FASEB J. 2007 Aug;21(10):2418-30. (PMID: 17384145)
      J Immunol. 2007 Jun 15;178(12):8138-47. (PMID: 17548652)
      Arthritis Rheum. 2007 Aug;56(8):2608-19. (PMID: 17665454)
      Circ Res. 2008 Apr 25;102(8):986-93. (PMID: 18323528)
      J Immunol. 2008 Oct 1;181(7):5082-8. (PMID: 18802112)
      Annu Rev Med. 2010;61:17-33. (PMID: 20059330)
      Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2307-12. (PMID: 20080612)
      Assay Drug Dev Technol. 2010 Dec;8(6):727-42. (PMID: 21158687)
      Br J Pharmacol. 2011 Dec;164(7):1847-56. (PMID: 21595651)
      Chem Rev. 2011 Oct 12;111(10):6209-30. (PMID: 21819041)
      Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3149-54. (PMID: 22323596)
      J Biol Chem. 2013 Mar 29;288(13):9293-302. (PMID: 23404506)
      J Med Chem. 2014 Jun 12;57(11):4454-65. (PMID: 24279689)
      J Clin Endocrinol Metab. 2014 Mar;99(3):1006-18. (PMID: 24471568)
      J Neurosci. 2014 Apr 23;34(17):5882-94. (PMID: 24760848)
      J Med Chem. 2014 May 22;57(10):4173-84. (PMID: 24773616)
      Eur J Med Chem. 2014 Jul 23;82:521-35. (PMID: 24937185)
      Neuropharmacology. 2015 Jun;93:15-27. (PMID: 25656476)
      J Med Chem. 2015 Jul 9;58(13):5256-73. (PMID: 26061158)
      Am J Vet Res. 2015 Oct;76(10):853-9. (PMID: 26413822)
      Neuropharmacology. 2016 Nov;110(Pt A):419-430. (PMID: 27477533)
      Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):E6427-E6436. (PMID: 28716915)
      Vet Med Sci. 2015 Dec 21;2(1):3-9. (PMID: 29067176)
      Life Sci. 1980 Aug 18;27(7):603-8. (PMID: 6999274)
      J Clin Invest. 1994 Mar;93(3):1095-101. (PMID: 8132748)
    • Grant Information:
      R01 NS097776 United States NS NINDS NIH HHS; R21 NS101167 United States NS NINDS NIH HHS; R33 NS101167 United States NS NINDS NIH HHS; U01 AG052460 United States AG NIA NIH HHS
    • Contributed Indexing:
      Keywords: EP2 antagonist; anti-inflammatory; aqueous-solubility; cytokines; lead-optimization; tetrazole
    • Accession Number:
      0 (Anti-Inflammatory Agents)
      0 (Inflammation Mediators)
      0 (PTGER2 protein, human)
      0 (Receptors, Prostaglandin)
      0 (Receptors, Prostaglandin E, EP2 Subtype)
      0 (Receptors, Prostaglandin E, EP4 Subtype)
      0 (prostanoid D receptor 1, human)
      059QF0KO0R (Water)
      K7Q1JQR04M (Dinoprostone)
    • Publication Date:
      Date Created: 20181107 Date Completed: 20190909 Latest Revision: 20220409
    • Publication Date:
      20240829
    • Accession Number:
      PMC6633905
    • Accession Number:
      10.1021/acs.molpharmaceut.8b00764
    • Accession Number:
      30398879