title: Discovery of heterocyclic sulfonamides as sphingosine 1-phosphate receptor 1 (S1P1) antagonists.
abstract: We have discovered a novel class of heterocyclic sulfonamides that act as antagonists of the S1P1 receptor. While members of this series identified from a high-throughput screen showed promising levels of potency in a cell-based assay measuring the inhibition of receptor internalization, most compounds were excessively lipophilic and contained an oxidation-prone thioether moiety. As a result, such compounds suffered from poor physical properties and metabolic stability, limiting their utility as in vivo probes. By removing the thioether group and systematically developing an understanding of structure-activity relationships and the effects of lipophilicity on potency within this series, we have been able to identify potent compounds with vastly improved physical properties. A representative enantiopure triazole sulfonamide (33) has measurable bioavailability following a low (3mg/kg) oral dose in rat, highlighting an achievement of the early hit-to-lead efforts for this series.
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Electronic address: edward.hennessy@astrazeneca.com.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hennessy
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Gurmit
authors.initials: G
authors.lastname: Grewal
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Byth
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Kamhi
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Danyang
authors.initials: D
authors.lastname: Li
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Lyne
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Vibha
authors.initials: V
authors.lastname: Oza
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Lucienne
authors.initials: L
authors.lastname: Ronco
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rooney
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Jamal C
authors.initials: JC
authors.lastname: Saeh
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Qibin
authors.initials: Q
authors.lastname: Su
mesh_terms: D000818:Animals; D055808:Drug Discovery; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D006571:Heterocyclic Compounds; D049349:Receptors, Lysosphingolipid; D013449:Sulfonamides
keywords: Heterocyclic sulfonamide; Lipophilic ligand efficiency; S1P(1) antagonist; Sphingosine 1-phosphate receptor 1