Indazole-6-phenyl­cyclopropyl­carboxylic Acids as Selective GPR120 Agonists with in Vivo Efficacy

GPR120
agonists have therapeutic potential for the treatment of
diabetes, but few selective agonists have been reported. We identified
an indazole-6-phenyl­cyclopropyl­carboxylic acid series
of GPR120 agonists and conducted SAR studies to optimize GPR120 potency.
Furthermore, we identified a (S,S)-cyclopropyl­carboxylic acid structural motif which gave selectivity
against GPR40. Good oral exposure was obtained with some compounds
displaying unexpected high CNS penetration. Increased MDCK efflux
was utilized to identify compounds such as 33 with lower
CNS penetration, and activity in oral glucose tolerance studies was
demonstrated. Differential activity was observed in GPR120 null and
wild-type mice indicating that this effect operates through a mechanism
involving GPR120 agonism.