title: Discovery of XEN907, a spirooxindole blocker of NaV1.7 for the treatment of pain.
abstract: Starting from the oxindole 2a identified through a high-throughput screening campaign, a series of Na(V)1.7 blockers were developed. Following the elimination of undesirable structural features, preliminary optimization of the oxindole C-3 and N-1 substituents afforded the simplified analogue 9b, which demonstrated a 10-fold increase in target potency versus the original HTS hit. A scaffold rigidification strategy then led to the discovery of XEN907, a novel spirooxindole Na(V)1.7 blocker. This lead compound, which in turn showed a further 10-fold increase in potency, represents a promising structure for further optimization efforts.
authors.affiliation: Department of Medicinal Chemistry, Xenon Pharmaceuticals Inc., Burnaby, British Columbia, Canada.
authors.forename: Sultan
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Mikhail
authors.initials: M
authors.lastname: Chafeev
authors.forename: Shifeng
authors.initials: S
authors.lastname: Liu
authors.forename: Jianyu
authors.initials: J
authors.lastname: Sun
authors.forename: Vandna
authors.initials: V
authors.lastname: Raina
authors.forename: Ray
authors.initials: R
authors.lastname: Chui
authors.forename: Wendy
authors.initials: W
authors.lastname: Young
authors.forename: Rainbow
authors.initials: R
authors.lastname: Kwan
authors.forename: Jianmin
authors.initials: J
authors.lastname: Fu
authors.forename: Jay A
authors.initials: JA
authors.lastname: Cadieux
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D062556:NAV1.7 Voltage-Gated Sodium Channel; D000078183:Oxindoles; D010146:Pain; D015222:Sodium Channels / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D007211:Indoles; D062556:NAV1.7 Voltage-Gated Sodium Channel; D000078183:Oxindoles; C486866:SCN9A protein, human; D015222:Sodium Channels; D013141:Spiro Compounds; C562355:XEN 907; C022960:2-oxindole