Design and synthesis of novel 2,3-dihydro-1H-isoindoles with high affinity and selectivity for the dopamine D3 receptor

Starting from the tetrahydroisoquinoline SB-277011 1, a novel series of 5-substituted-2,3-dihydro-1H-isoindoles has been designed. Subsequent optimisation resulted in identification of 19, which has high affinity for the dopamine D3 receptor (pKi 8.3) and ≥100-fold selectivity over other aminergic receptors. In rat studies 19 was brain penetrant with an excellent pharmacokinetic profile (oral bioavailability 77%, t12 5.2h).