N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists II.
Introduction of selected amine containing side chains into the 3-position of N',2-diphenylquinoline-4-carbohydrazide based NK3 antagonists abolishes unwanted hPXR activation. Introduction of a fluorine at the 8-position is necessary to minimize unwanted hI(Kr) affinity and a piperazine N-tert-butyl group is necessary for metabolic stability. The lead compound (8m) occupies receptors within the CNS following oral dosing (Occ(90) 7 mg/kg po; plasma Occ(90) 0.4 microM) and has good selectivity and excellent PK properties.
Elliott
Jason M
JM
Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. jason@elliottj25.fsnet.co.uk
Carling
Robert W
RW
Chicchi
Gary G
GG
Crawforth
James
J
Hutson
Peter H
PH
Jones
A Brian
AB
Kelly
Sarah
S
Marwood
Rose
R
Meneses-Lorente
Georgina
G
Mezzogori
Elena
E
Murray
Fraser
F
Rigby
Michael
M
Royo
Inmaculada
I
Russell
Michael G N
MG
Shaw
Duncan
D
Sohal
Bindi
B
Tsao
Kwei Lan
KL
Williams
Brian
B
D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005461:Fluorine / Q000737:chemistry* / Q000494:pharmacology; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D006834:Hydrazines; C515787:N-((methoxycarbonyl)(phenyl)amino)-3-(4-tert-butylpiperazin-1-ylmethyl)-8-fluoro-2-phenylquinoline-4-carboxamide; D018377:Neurotransmitter Agents; D010879:Piperazines; D011804:Quinolines; D018042:Receptors, Neurokinin-3; D005461:Fluorine; C019289:carbohydrazide