Navigating CYP1A Induction and Arylhydrocarbon Receptor Agonism in Drug Discovery. A Case History with S1P1 Agonists.

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
    • Publication Information:
      Publication: Washington Dc : American Chemical Society
      Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
    • Subject Terms:
      Cytochrome P-450 CYP1A1/*biosynthesis ; Cytochrome P-450 CYP1A2/*biosynthesis ; Enzyme Induction/*drug effects ; Receptors, Aryl Hydrocarbon/*agonists ; Receptors, Lysosphingolipid/*agonists; Animals ; Dogs ; Drug Design ; Drug Discovery ; Hepatocytes/drug effects ; Humans ; Lipids/chemistry ; Macaca fascicularis ; Mice ; Models, Molecular ; RNA, Messenger/biosynthesis ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship ; Up-Regulation/drug effects
    • Abstract:
      This article describes the finding of substantial upregulation of mRNA and enzymes of the cytochrome P450 1A family during a lead optimization campaign for small molecule S1P1 agonists. Fold changes in mRNA up to 10,000-fold for CYP1A1 in vivo in rat and cynomolgus monkey and up to 45-fold for CYP1A1 and CYP1A2 in vitro in rat and human hepatocytes were observed. Challenges observed with correlating induction in vitro and induction in vivo resulted in the implementation of a short, 4 day in vivo screening study in the rat which successfully identified noninducers. Subtle structure-activity relationships in this series of S1P1 agonists are described extending beyond planarity and lipophilicity, and the impact and considerations of AhR and CYP1A induction in the context of drug development are discussed.
    • Accession Number:
      0 (Lipids)
      0 (RNA, Messenger)
      0 (Receptors, Aryl Hydrocarbon)
      0 (Receptors, Lysosphingolipid)
      EC 1.14.14.1 (Cytochrome P-450 CYP1A1)
      EC 1.14.14.1 (Cytochrome P-450 CYP1A2)
    • Publication Date:
      Date Created: 20150923 Date Completed: 20160202 Latest Revision: 20151022
    • Publication Date:
      20240829
    • Accession Number:
      10.1021/acs.jmedchem.5b01102
    • Accession Number:
      26393276