Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB2) agonists.
The CB2 receptor is an attractive therapeutic target for analgesic and anti-inflammatory agents. Herein we describe the discovery of a novel class of oxadiazole derivatives from which potent and selective CB2 agonist leads were developed. Initial hit 7 was identified from a cannabinoid target-biased library generated by virtual screening of sample collections using a pharmacophore model in combination with a series of physicochemical filters. 7 was demonstrated to be a selective CB2 agonist (CB2 EC50 = 93 nM, Emax = 98%, CB1 EC50 > 10 microM). However, this compound exhibited poor solubility and relatively high clearance in rat, resulting in low oral bioavailability. In this paper, we report detailed SAR studies on 7 en route toward improving potency, physicochemical properties, and solubility. This effort resulted in identification of 63 that is a potent and selective agonist at CB2 (EC50 = 2 nM, Emax = 110%) with excellent pharmacokinetic properties.
Cheng
Yuan
Y
Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. yuanc@amgen.com
Albrecht
Brian K
BK
Brown
James
J
Buchanan
John L
JL
Buckner
William H
WH
DiMauro
Erin F
EF
Emkey
Renee
R
Fremeau
Robert T
RT
Harmange
Jean-Christophe
JC
Hoffman
Beth J
BJ
Huang
Liyue
L
Huang
Ming
M
Lee
Josie Han
JH
Lin
Fen-Fen
FF
Martin
Matthew W
MW
Nguyen
Hung Q
HQ
Patel
Vinod F
VF
Tomlinson
Susan A
SA
White
Ryan D
RD
Xia
Xiaoyang
X
Hitchcock
Stephen A
SA
D000284:Administration, Oral; D000634:Aminoquinolines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008958:Models, Molecular; D010069:Oxadiazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013329:Structure-Activity Relationship
C531231:6-chloro-N-(3-(3-(2-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5-yl)propyl)quinolin-3-amine; D000634:Aminoquinolines; D010069:Oxadiazoles; D043885:Receptor, Cannabinoid, CB2