Spirocyclic delta opioid receptor agonists for the treatment of pain: discovery of N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4'-piperidine]-4-yl) benzamide (ADL5747).
Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.
Le Bourdonnec
Bertrand
B
Departments of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, Pennsylvania 19341, USA. blebourdonnec@adolor.com
Windh
Rolf T
RT
Leister
Lara K
LK
Zhou
Q Jean
QJ
Ajello
Christopher W
CW
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
Derelanko
Michael J
MJ
Kutz
Steve
S
Little
Patrick J
PJ
DeHaven
Robert N
RN
DeHaven-Hudkins
Diane L
DL
Dolle
Roland E
RE
D000700:Analgesics / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D001578:Benzopyrans / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D016466:CHO Cells; D002986:Clinical Trials as Topic; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*
D000700:Analgesics; D001549:Benzamides; D001578:Benzopyrans; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C544196:N,N-diethyl-3-hydroxy-4-(spiro(chromene-2,4'-piperidine)-4-yl)benzamide; D017465:Receptors, Opioid, delta; D013141:Spiro Compounds