Kevin Pan

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.

The Synthesis of Aminobenzothiazoles from 2,3-Biaryl-5-anilino-Δ3-1,2,4-thiadiazolines

Abstract 2-Amidinobenzothiazoles 4 can be prepared in high yields by a thermally-promoted rearrangement of thiadiazolium salts 1 or thiadiazolines 2. Addition of base to the rearrangement of the thiadiazolium salts can improve the yields by the prior conversion of the thiadiazolium salts to the corresponding thiadiazoline free bases. The rearrangement of the thiadiazolines may go through an electrophilic aromatic substitution or free radical pathway.