Discovery of selective biaryl ethers as PDE10A inhibitors: Improvement in potency and mitigation of Pgp-mediated efflux

We report the discovery of a novel series of biaryl ethers as potent and selective PDE10A inhibitors. Structure-activity studies improved the potency and decreased Pgp-mediated efflux found in the initial compound 4. X-ray crystallographic studies revealed two novel binding modes to the catalytic site of the PDE10A enzyme.