2,3-Diaryl-5-anilino[1,2,4]thiadiazoles as melanocortin MC4 receptor agonists and their effects on feeding behavior in rats.
The melanocortin-4 receptor (MC4) modulates physiological functions such as feeding behavior, nerve regeneration, and drug addiction. Using a high throughput screen based on (125)I-NDP-MSH binding to the human MC4 receptor, we discovered 2,3-diaryl-5-anilino[1,2,4]thiadiazoles 3 as potent and selective MC4 receptor agonists. Through SAR development on the three attached aryl rings, we improved the binding affinity from 174 nM to 4.4 nM IC(50). When delivered intraperitoneally, compounds 3a, 3b, and 3c induced significant inhibition of food intake in a fasting-induced feeding model in rats. When delivered orally, these compounds lost activity, mainly due to rapid metabolism to inactive imidoylthiourea reduction products.
Pan
Kevin
K
Drug Discovery Division, Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Rds., PO Box 776, Spring House, PA 19477, USA.
Scott
Malcolm K
MK
Lee
Daniel H S
DH
Fitzpatrick
Louis J
LJ
Crooke
Jeffery J
JJ
Rivero
Ralph A
RA
Rosenthal
Daniel I
DI
Vaidya
Anil H
AH
Zhao
Boyu
B
Reitz
Allen B
AB
D000818:Animals; D004195:Disease Models, Animal; D005215:Fasting / Q000502:physiology; D005247:Feeding Behavior / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007263:Infusions, Parenteral; D020128:Inhibitory Concentration 50; D007457:Iodine Radioisotopes; D008297:Male; D008545:Melanoma / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000378:metabolism
D007457:Iodine Radioisotopes; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D013830:Thiadiazoles; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-