oral full agonist of GPR40 GCPR
oral efficacy in obesity model, entered Ph. I
from optimization of prior molecule
J. Med. Chem., Sep. 24, 2020
Takeda / SCOHIA Pharma, Fujisawa, JP
SCO-267 is a full agonist of the GPCR GPR40, whose activation stimulates secretions of insulin and incretin. Since no crystal structures were available, the authors used conformational modeling to rationally improve the ligand from a weak lipophilic initial starting point (0.4 uM, clogP 9.4) to a more lipophilically efficient candidate (12 nM, clogP = 5.8). The compound is orally active in a rodent obesity model and was advanced to a Ph. I study.