2-Aryl indole NK(1) antagonists: optimisation of the amide substituent.
The in vivo properties of a series of 2-arylindole NK(1) antagonists have been improved, by modification of the amide substituent. The 1-(2-methoxyphenyl)piperazine amide was identified as a major area of metabolism in the lead compound 1. Replacement of this amine moiety by a 4-benzyl-4-hydroxypiperidine resulted in a compound 18 with reduced clearance and improved central duration of action.
Shaw
D
D
Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. duncan_shaw@merck.com
Chicchi
G G
GG
Elliott
J M
JM
Kurtz
M
M
Morrison
D
D
Ridgill
M P
MP
Szeto
N
N
Watt
A P
AP
Williams
A R
AR
Swain
C J
CJ
D000284:Administration, Oral; D000577:Amides / Q000737:chemistry*; D000818:Animals; D001682:Biological Availability; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D007211:Indoles / Q000493:pharmacokinetics*; D020128:Inhibitory Concentration 50; D008657:Metabolic Clearance Rate; D015288:Neurokinin A / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship
C448359:1-(2-methoxyphenyl)piperazine amide; D000577:Amides; D007211:Indoles; D010879:Piperazines; D015288:Neurokinin A