Structure-activity relationships of a series of benzothiophene-derived NPY Y1 antagonists: optimization of the C-2 side chain.
A series of benzo[b]thiophene-derived NPY-1 receptor antagonists is described. Systematic modification of the C-2 substituent afforded a 1000-fold range in Y1 receptor affinity. Appropriate substitution at the ortho and para positions of the C-2 phenyl ether produced a synergistic effect on Y1 binding affinity, which led to the discovery of the most active ligands, 12t (K(i) = 15 nM), 12u (K(i) = 11 nM), and 12v (K(i) = 13 nM).
Britton
T C
TC
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Spinazze
P G
PG
Hipskind
P A
PA
Zimmerman
D M
DM
Zarrinmayeh
H
H
Schober
D A
DA
Gehlert
D R
DR
Bruns
R F
RF
D066298:In Vitro Techniques; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
D017476:Receptors, Neuropeptide Y; D011994:Recombinant Proteins; D013876:Thiophenes; C097212:neuropeptide Y-Y1 receptor; C088015:benzothiophene