title: Navigating CYP1A Induction and Arylhydrocarbon Receptor Agonism in Drug Discovery. A Case History with S1P1 Agonists.
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.
authors.affiliation: Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Taylor
authors.affiliation: Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Emmanuel H
authors.initials: EH
authors.lastname: Demont
authors.affiliation: Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: James
authors.initials: J
authors.lastname: Gray
authors.affiliation: Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Nigel
authors.initials: N
authors.lastname: Deeks
authors.affiliation: PTS DMPK, GlaxoSmithKline , Park Road, Ware, SG12 0DP, U.K.
authors.forename: Aarti
authors.initials: A
authors.lastname: Patel
authors.affiliation: PTS DMPK, GlaxoSmithKline , Upper Merion, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Dung
authors.initials: D
authors.lastname: Nguyen
authors.affiliation: PTS DMPK, GlaxoSmithKline , Park Road, Ware, SG12 0DP, U.K.
authors.forename: Maxine
authors.initials: M
authors.lastname: Taylor
authors.affiliation: PTS DMPK, GlaxoSmithKline , Park Road, Ware, SG12 0DP, U.K.
authors.forename: Steve
authors.initials: S
authors.lastname: Hood
authors.affiliation: Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Watson
authors.affiliation: Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Rino A
authors.initials: RA
authors.lastname: Bit
authors.affiliation: Safety Assessment, GlaxoSmithKline , Park Road, Ware, SG12 0DP, U.K.
authors.forename: Fiona
authors.initials: F
authors.lastname: McClure
authors.affiliation: Safety Assessment, GlaxoSmithKline , Park Road, Ware, SG12 0DP, U.K.
authors.forename: Holly
authors.initials: H
authors.lastname: Ashall
authors.affiliation: Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Jason
authors.initials: J
authors.lastname: Witherington
mesh_terms: D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D004285:Dogs; D015195:Drug Design; D055808:Drug Discovery; D004790:Enzyme Induction / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008252:Macaca fascicularis; D051379:Mice; D008958:Models, Molecular; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D008055:Lipids; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D049349:Receptors, Lysosphingolipid; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2