Potent, orally bioavailable delta opioid receptor agonists for the treatment of pain: discovery of N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4'-piperidine]-4-yl)benzamide (ADL5859).
Selective delta opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable delta agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.
Le Bourdonnec
Bertrand
B
Department of Chemistry, Adolor Corporation, Exton, Pennsylvania 19341, USA. blebourdonnec@adolor.com
Windh
Rolf T
RT
Ajello
Christopher W
CW
Leister
Lara K
LK
Gu
Minghua
M
Chu
Guo-Hua
GH
Tuthill
Paul A
PA
Barker
William M
WM
Koblish
Michael
M
Wiant
Daniel D
DD
Graczyk
Thomas M
TM
Belanger
Serge
S
Cassel
Joel A
JA
Feschenko
Marina S
MS
Brogdon
Bernice L
BL
Smith
Steven A
SA
Christ
David D
DD
Derelanko
Michael J
MJ
Kutz
Steve
S
Little
Patrick J
PJ
DeHaven
Robert N
RN
DeHaven-Hudkins
Diane L
DL
Dolle
Roland E
RE
D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D001578:Benzopyrans / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D001682:Biological Availability; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists*; D018675:Toxicity Tests
D000700:Analgesics; D001549:Benzamides; D001578:Benzopyrans; D051638:Ether-A-Go-Go Potassium Channels; C532570:N,N-diethyl-4-(5-hydroxyspiro(chromene-2,4'-piperidine)-4-yl)benzamide; D017465:Receptors, Opioid, delta