Delta agonist hydroxy bioisosteres: the discovery of 3-((1-benzylpiperidin-4-yl){4-[(diethylamino)carbonyl]phenyl}amino)benzamide with improved delta agonist activity and in vitro metabolic stability.
We have investigated phenol replacements in a series of diaryl amino piperidine delta opioid agonists. From this study we have demonstrated that the hydroxy functional group can be replaced with a primary amide group, giving enhanced activity at the delta receptor, increased selectivity versus mu and kappa as well as improved in vitro metabolic stability.
Griffin
Andrew M
AM
Department of Medicinal Chemistry, AstraZeneca R&D Montréal, 7171 Frédérick-Banting, Ville St. Laurent, Québec, Canada H4S 1Z9. andrew.griffin@astrazeneca.com
Brown
William
W
Walpole
Christopher
C
Coupal
Martin
M
Adam
Lynda
L
Gosselin
Mylene
M
Salois
Dominic
D
Morin
Pierre-Emmanuel
PE
Roumi
Marie
M
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000700:Analgesics; D010880:Piperidines; D017465:Receptors, Opioid, delta; C032727:piperidine; D004159:Diphenylamine