4-Amino-2-(aryl)-butylbenzamides and Their conformationally constrained analogues. Potent antagonists of the human neurokinin-2 (NK(2)) receptor.
A library, evaluating a range of piperazines, piperidines and acyclic amines, as replacements for the 4-hydroxy-4-phenylpiperidine moiety in lead (1b) was prepared. These efforts identified the 4-((N)-benzimidazolone)piperidine analogue (2a) which was further optimised using classical single-compound synthesis to yield the 3-((N)-morpholino)azetidine (2j). Conformationally constrained analogues of (2j), generally offered no potency advantage in this particular series.
MacKenzie
A Roderick
AR
Department of Discovery Chemistry, Pfizer Global Research and Development, CT13 9NJ, Sandwich, Kent, UK.
Marchington
Allan P
AP
Middleton
Donald S
DS
Newman
Sandra D
SD
Selway
Christopher N
CN
Terrett
Nicholas K
NK
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003500:Cyclization; D015195:Drug Design; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008968:Molecular Conformation; D019151:Peptide Library; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry; D051381:Rats; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D001549:Benzamides; D019151:Peptide Library; D010880:Piperidines; D018041:Receptors, Neurokinin-2