title: Fused bicyclic pyrrolizinones as new scaffolds for human NK1 antagonists.
abstract: Previous work on human NK(1) antagonists in which the core of the structure is a substituted pyrrolidine has been disclosed. These compounds showed good binding affinity and functional IP activity, however, many did not exhibit the necessary brain penetration for good in vivo activity. The discovery and preparation of a novel 5,5-fused pyrrolidine core is presented in this paper. This scaffold maintains the excellent binding affinity and functional IP activity of the previously reported compounds, but also exhibits excellent brain penetration as observed in a gerbil foot-tapping assay. The determination of the core structural stereochemistry, which eventually led to the final synthesis of a single active diastereomer, is described.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Gregori J
authors.initials: GJ
authors.lastname: Morriello
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Devita
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Young
authors.forename: Peter
authors.initials: P
authors.lastname: Lin
authors.forename: George
authors.initials: G
authors.lastname: Doss
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: Julie
authors.initials: J
authors.lastname: Demartino
authors.forename: Marc M
authors.initials: MM
authors.lastname: Kurtz
authors.forename: Kwei-Lan C
authors.initials: KL
authors.lastname: Tsao
authors.forename: Emma
authors.initials: E
authors.lastname: Carlson
authors.forename: Karen
authors.initials: K
authors.lastname: Townson
authors.forename: Alan
authors.initials: A
authors.lastname: Wheeldon
authors.forename: Susan
authors.initials: S
authors.lastname: Boyce
authors.forename: Neil
authors.initials: N
authors.lastname: Collinson
authors.forename: Nadia
authors.initials: N
authors.lastname: Rupniak
authors.forename: Stephen
authors.initials: S
authors.lastname: Moore
mesh_terms: D000577:Amides / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000737:chemistry; D006801:Humans; D006900:Hydroxylation; D008745:Methylation; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013237:Stereoisomerism; D014508:Urea / Q000737:chemistry
chemical_list: D000577:Amides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004852:Epoxy Compounds; D064729:Neurokinin-1 Receptor Antagonists; D011758:Pyrroles; D018040:Receptors, Neurokinin-1; D014508:Urea