Download MendeleyDiscovery of a Potent, Selective and Orally Active Pde10A Inhibitor for the Potential Treatment of Schizophrenia.
Bartolome-Nebreda, J.M., Delgado, F., Martin, M.L., Martinez-Viturro, C.M., Pastor, J., Tong, H.M., Iturrino, L., Macdonald, G.J., Sanderson, W.E., Megens, A., Langlois, X., Somers, M., Vanhoof, G., Conde Ceide, S.(2014) J Med Chem 57: 4196
- PubMed: 24758746
- DOI: https://doi.org/10.1021/jm500073h
- Primary Citation of Related Structures:
4BBX - PubMed Abstract:
We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure-activity and structure-property relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats.
Organizational Affiliation:
Neuroscience Medicinal Chemistry and ‡Discovery Sciences Analytical Sciences, Janssen Research & Development , Calle Jarama 75, Polígono Industrial, Toledo 45007, Spain.
