Discovery of cariprazine (RGH-188): A novel antipsychotic acting on dopamine D3/D2 receptors

Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide type dopamine D-3/D-2 compound (1) led to a series of new piperazine derivatives having affinity to both dopamine D-3 and D-2 receptors. Several members of this group showed excellent pharmacokinetic and pharmacodynamic properties as demonstrated by outstanding activities in different antipsychotic tests. The most promising representative, 2m (cariprazine) had good absorption, excellent brain penetration and advantageous safety profile. Based on its successful clinical development we are looking forward to the NDA filing of cariprazine in 2012. (C) 2012 Elsevier Ltd. All rights reserved.