Schizophrenia involves diminished or altered motivation, deficits in social behavior, and difficulties with complex cognitive tasks. Patients often manage their psychoses to some degree with prescription antipsychotics, but there are no effective therapies for the negative and cognitive symptoms, which remain significant unmet medical needs. <br/>The habenula is a small nucleus that gates information flow from higher brain centers to the monoaminergic nuclei of the midbrain and brainstem, and is essential for assigning negative value to unrewarding situations. Lesions of the habenula cause deficits in social behavior and cognitive ability, and in schizophrenics, the habenula fails to activate when the patient is challenged with a negative reward. We identified the orphan G-protein coupled receptor GPR139 as a novel excitatory Gq-coupled receptor enriched in the dorsal medial habenula, a small subregion in the habenula that has not been studied extensively. Thus, agonists of GPR139 have the potential to be first-in-class therapies for the treatment of psychiatric diseases with debilitating deficits in social domains such as negative symtoms of schizophrenia.<br/>High-throughput screening of GPR139 yielded promising starting points for medicinal chemistry, which rapidly led to the development of compounds with sufficient potency, selectivity, and brain-penetration to be useful as in vivo tool molecules. In vivo target validation as well as strategies towards the confirmation of in vivo target engagement and PK/PD will be presented in the talk. Last but not least, the first-in-class Takeda GPR139 agonist and FIH molecule will be revealed for the first time.

Discovery of TAK-041: Potent and selective GPR139 agonist for treatment of negative symptoms associated with schizophrenia

254th National Meeting (2017)

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