title: 2-Aryl indole NK(1) antagonists: optimisation of the amide substituent.
abstract: 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.
authors.affiliation: 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
authors.forename: D
authors.initials: D
authors.lastname: Shaw
authors.forename: G G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: J M
authors.initials: JM
authors.lastname: Elliott
authors.forename: M
authors.initials: M
authors.lastname: Kurtz
authors.forename: D
authors.initials: D
authors.lastname: Morrison
authors.forename: M P
authors.initials: MP
authors.lastname: Ridgill
authors.forename: N
authors.initials: N
authors.lastname: Szeto
authors.forename: A P
authors.initials: AP
authors.lastname: Watt
authors.forename: A R
authors.initials: AR
authors.lastname: Williams
authors.forename: C J
authors.initials: CJ
authors.lastname: Swain
mesh_terms: 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
chemical_list: C448359:1-(2-methoxyphenyl)piperazine amide; D000577:Amides; D007211:Indoles; D010879:Piperazines; D015288:Neurokinin A