title: Hit-to-lead evaluation of a novel class of sphingosine 1-phosphate lyase inhibitors.
abstract: Inhibition of sphingosine-1-phosphate lyase has recently been proposed as a potential treatment option for inflammatory disorders such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. In this report we describe our hit-to-lead evaluation of the isoxazolecarboxamide 6, a high-throughput screening hit (in vitro IC50=1.0 μM, cell IC50=1.8 μM), as a novel S1P lyase inhibitor. We were able to establish basic structure-activity relationships around 6 and succeeded in obtaining X-ray structural information which enabled structure-based design. With the discovery of 28, enzyme activity was quickly improved to IC50=120 nM and cell potency to IC50=230 nM. The main liability in the established isoxazolecarboxamide hit series was determined to be metabolic stability. In particular we identified that future lead-optimization efforts to overcome this problem should focus on blocking the N-dealkylation on the secondary amine.
authors.affiliation: AbbVie Inc., 1 North Waukegan Road, IL 60064, USA.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Dinges
authors.affiliation: AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Harris
authors.affiliation: AbbVie Bioresearch Center, 381 Plantation Street, Worcester, MA 01605, USA.
authors.forename: Grier A
authors.initials: GA
authors.lastname: Wallace
authors.affiliation: AbbVie Bioresearch Center, 381 Plantation Street, Worcester, MA 01605, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Argiriadi
authors.affiliation: AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Queeney
authors.affiliation: AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
authors.forename: Denise C
authors.initials: DC
authors.lastname: Perron
authors.affiliation: AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Dominguez
authors.affiliation: AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
authors.forename: Tegest
authors.initials: T
authors.lastname: Kebede
authors.affiliation: AbbVie Inc., 1 North Waukegan Road, IL 60064, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Desino
authors.affiliation: AbbVie Inc., 1 North Waukegan Road, IL 60064, USA.
authors.forename: Hetal
authors.initials: H
authors.lastname: Patel
authors.affiliation: AbbVie Inc., 1 North Waukegan Road, IL 60064, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Vasudevan
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase)
keywords: Hit-to-lead; Inhibitor; Parallel synthesis; Sphingosine 1-phosphate lyase; Structure-based design