2-Aryl indole NK1 antagonists: optimisation of the amide substituent

The in vivo properties of a series of 2-arylindole NK1 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.