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.
Discovery Research, Eli Lilly and Company, Indianapolis, IN 46285, USA. diaz_nuria@lilly.com
Nuria
N
Díaz
Mark
M
Benvenga
Paul
P
Emmerson
Ryan
R
Favors
Michael
M
Mangold
Jamie
J
McKinzie
Nita
N
Patel
Steven
S
Peters
Steven
S
Quimby
Harlan
H
Shannon
Miles
M
Siegel
Michael
M
Statnick
Elizabeth
E
Thomas
Joseph
J
Woodland
Peggy
P
Surface
Charles
C
Mitch
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