Phosphodiesterases (PDEs) are intracellular enzymes involved in the hydrolysis of cAMP and/or cGMP into their respective nucleotide monophosphates. Phosphodiesterase 10A (PDE10A) is expressed at high levels in striatal medium spiny neurons. This tissue distribution pattern suggests that selective inhibition of PDE10A could be used to raise levels of cAMP and/or cGMP within cells and, therefore, may be useful in treating a variety of neuropsychiatric conditions, such as schizophrenia. High throughput screening (HTS) of our in-house chemical library identified a pyridazin-4(1H)-one derivative with a PDE10A IC50 of 23 nM and 110-fold selectivity against other PDEs. Structural optimization was supported by crystal structures obtained for multiple complexes of pyridazin-4(1H)-one derivatives with PDE10A. The X-ray analysis indicated two primary hydrogen bonds: in addition to a common hydrogen bond with the pyridazin-4(1H)-one oxygen to conserved glutamine residue Gln716 in all PDE isoforms, an interaction between the pyrazole nitrogen and Tyr514 (specific to PDE10) via a water molecule was detected. PDE10A inhibitory activity was improved by the introduction of a methoxy group at the 5-position of the pyridazin-4(1H)-ones. 5-Methoxypyridazin-4(1H)-one served as a bidentate ligand to Gln716 in the X-ray crystal structures. In addition, introduction of substituents at the para position of the phenyl rings resulted in significant improvement in affinity and selectivity. The resulting molecule, TAK-063, has a PDE10A IC50 of 0.30 nM and &gt;15000-fold selectivity against all other PDEs. TAK-063 is currently under evaluation in clinical trials for the treatment of schizophrenia.

Discovery of TAK-063, a novel phosphodiesterase 10A (PDE10A) inhibitor

249th National Meeting (2015)

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