Pyrrolidine-carboxamides and oxadiazoles as potent hNK1 antagonists.
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.
Young
Jonathan R
JR
Department of Medicinal Chemistry, Merck Research Laboratories, PO 2000, Rahway, NJ 07065-0900, USA. jonathan_young@merck.com
Eid
Ronsar
R
Turner
Cherilyn
C
DeVita
Robert J
RJ
Kurtz
Marc M
MM
Tsao
Kwei-Lan C
KL
Chicchi
Gary G
GG
Wheeldon
Alan
A
Carlson
Emma
E
Mills
Sander G
SG
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
D000470:Alkaloids; D000998:Antiviral Agents; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D010069:Oxadiazoles; D011759:Pyrrolidines