title: Tetrahydroindolizinone NK1 antagonists.
abstract: A new class of potent NK(1) receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK(1) receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK(1) binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P(450) inhibition and hPXR induction profiles.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. bao_jianming@merck.com
authors.forename: Jianming
authors.initials: J
authors.lastname: Bao
authors.forename: Huagang
authors.initials: H
authors.lastname: Lu
authors.forename: Gregori J
authors.initials: GJ
authors.lastname: Morriello
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Carlson
authors.forename: Alan
authors.initials: A
authors.lastname: Wheeldon
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: Marc M
authors.initials: MM
authors.lastname: Kurtz
authors.forename: Kwei-Lan C
authors.initials: KL
authors.lastname: Tsao
authors.forename: Song
authors.initials: S
authors.lastname: Zheng
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Robert J
authors.initials: RJ
authors.lastname: DeVita
mesh_terms: D000818:Animals; D005849:Gerbillinae; D006801:Humans; D007212:Indolizines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D007212:Indolizines; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1