title: Pyrrolidine-carboxamides and oxadiazoles as potent hNK1 antagonists.
abstract: The preparation and structure-activity-relationships of novel pyrrolidine-carboxamides and oxadiazoles are described. Compounds in this series were found to be potent hNK(1) antagonists in vitro and efficacious in vivo with minimal interactions with P(450) liver enzymes. Oxadiazole analog 22 was determined to have excellent hNK(1) binding affinity, functional activity, and a good PD response in vivo.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO 2000, Rahway, NJ 07065-0900, USA. jonathan_young@merck.com
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Young
authors.forename: Ronsar
authors.initials: R
authors.lastname: Eid
authors.forename: Cherilyn
authors.initials: C
authors.lastname: Turner
authors.forename: Robert J
authors.initials: RJ
authors.lastname: DeVita
authors.forename: Marc M
authors.initials: MM
authors.lastname: Kurtz
authors.forename: Kwei-Lan C
authors.initials: KL
authors.lastname: Tsao
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: Alan
authors.initials: A
authors.lastname: Wheeldon
authors.forename: Emma
authors.initials: E
authors.lastname: Carlson
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002852:Chromatography, Ion Exchange; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006513:Hepatitis B e Antigens / Q000378:metabolism; D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D029583:Menispermaceae / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000470:Alkaloids; D000998:Antiviral Agents; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D010069:Oxadiazoles; D011759:Pyrrolidines