Design,Synthesis And Antipsychotic Study Of PDE10A Inhibitors

Schizophrenia,a kind of common and severe mental illness characterized by high morbidity and recurrence rate,causes serious medical and social problems nowadays.Antipsychotic drugs currently used in the treatment of schizophrenia patients still have great limitations in improving negative symptoms,cognitive dysfunction and reducing side effects.The pathogenesis of schizophrenia is not clear currently,but in recent years,more and more evidences indicate that phosphodiesterases?PDEs?play very important roles in the etiology and treatment of schizophrenia.cAMP?3?,5?-cyclic adenosine monophosphate?and cGMP?3?,5?-cyclic guanosine monophosphate?are second messengers within cells.The generation and resulting regulation of this signaling are important to many functions throughout the cell,including vision,memory,immune response and learning.Researchers found an intimately link between schizophrenia and the low levels of cAMP or cGMP.PDEs are the key enzymes of degradation of cAMP and cGMP,therefore the PDE inhibitors are able to increase the cAMP and cGMP to reach the normal levels by inhibiting the hydrolysis of cAMP and cGMP,so as to achieve the treatment of schizophrenia.Phosphodiesterases are subdivided into 11 distinct families according to structural and functional properties phosphodiesterase10A?PDE10A?has the most restricted distribution with high expression in the striatal medium spiny neurons?MSNs?,which indicates that PDE10A participates in the pathogenic course related to striatum dysfunction.clinical evidences manifest that selective PDE10A inhibitors can treat the negative symptoms and cognitive dysfunction of schizophrenia.We have previously reported the synthesis of multi-substituted 8-aminoimidazo[1,2-a]pyrazine by Groebke–Blackburn–Bienayméreaction.Based on the same8-aminoimidazo[1,2-a]pyrazines structure of the S2,a PDE10A inhibitor reported by Joséet al.We tested PDE10A inhibitory activity on the series of8-aminoimidazo[1,2-a]pyrazines compounds,leading to a compound RJ-1 with potent activity(IC₅₀=447 nM).Medicinal chemistry optimization of the hit RJ-1 led to the discovery of compounds 67 and 71 with in vitro potent inhibitory activity against PDE10A and in vivo efficacy in antipsychotic models.They also showed a good metabolic stability profile in the liver microsomes of rat and human.From multi-substituted 8-aminoimidazo[1,2-a]pyrazines,prepared via modified Groebke–Blackburn–Bienayméreaction,a Pd-catalyzed cyclization reaction was discovered,generating a rare?Z?-4,5-dihydro-3H-[1,3]diazocine system.Conditions of this cyclization were screened and DMF solvent was found to be one of the key factors for the cyclization.