Author: Webb, Maria ; Stein, Philip ; Fanelli, Barbara ; Ebert-Gallo, Christina ; Beasley, James ; Li, Yanfang ; Cole, Andrew ; Hayward, Michael ; Tovar, Kiersten ; Huang, Chia-Yu ; Ma, Xiaoquing ; Nickels, Joseph ; Healy, Jason ; McGuinness, Brian ; Kultgen, Steven ; Nawoschik, Stanley ; Shi, Dongchuan
G-protein coupled bile acid receptor 1(GPBAR1, also known as TGR5) agonism increases energy expenditure and lowers blood glucose, thus GPBAR1 has attracted interests as a target for treating human metabolic diseases.A sulfonamide based chem. series was identified as an attractive starting point from screen of our ECLiPS compound collection.Since TGR5 activation was linked to gallbladder filling and some cardiovascular side effects, the goal of our lead optimization effort was to identify potent agonists with minimal systemic exposure.This led to some potent and minimally exposed TGR5 agonists.