SAR and biological evaluation of novel trans-3,4-dimethyl-4-arylpiperidine derivatives as opioid antagonists.
The phenolic hydroxy group of opiate-derived ligands is of known importance for biological activity. We have developed a SAR study around LY255582 by comparing the effect of the hydroxy group in the 2- and 4-position of the phenyl ring. Also, we have proved that the 3-position of the phenyl ring is optimal for opioid activity. Furthermore, we have successfully replaced the hydroxy group in LY255582 by carbamate and carboxamide groups. The new analogs have high affinity for the opioid receptors comparable to the corresponding phenol. Carboxamide analog 12 has an improved metabolism profile and proved to be efficacious in in vivo studies.
Díaz
Nuria
N
Discovery Research, Eli Lilly and Company, Indianapolis, IN 46285, USA. diaz_nuria@lilly.com
Benvenga
Mark
M
Emmerson
Paul
P
Favors
Ryan
R
Mangold
Michael
M
McKinzie
Jamie
J
Patel
Nita
N
Peters
Steven
S
Quimby
Steven
S
Shannon
Harlan
H
Siegel
Miles
M
Statnick
Michael
M
Thomas
Elizabeth
E
Woodland
Joseph
J
Surface
Peggy
P
Mitch
Charles
C
D000284:Administration, Oral; D000818:Animals; D003510:Cyclohexanes; D004353:Drug Evaluation, Preclinical; D005247:Feeding Behavior / Q000187:drug effects; D008024:Ligands; D008099:Liver / Q000378:metabolism; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010146:Pain / Q000517:prevention & control; D010636:Phenols; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D013329:Structure-Activity Relationship
D003510:Cyclohexanes; D008024:Ligands; D009292:Narcotic Antagonists; D010636:Phenols; D010880:Piperidines; C070736:LY 243670