4BBX

Discovery of a potent, selective and orally active PDE10A inhibitor for the treatment of schizophrenia

Summary for 4BBX

• Entry DOI: 10.2210/pdb4bbx/pdb
• Related: 1LRB 2WEY 2Y0J 4AEL 4AJD 4AJF 4AJG 4AJM
• Descriptor: CAMP AND CAMP-INHIBITED CGMP 3', 5'-CYCLIC PHOSPHODIESTERASE 10A, 4-[3-[1-[(2S)-2-methoxypropyl]pyrazol-4-yl]-2-methyl-imidazo[1,2-a]pyrazin-8-yl]morpholine, ZINC ION, ... (5 entities in total)
• Functional Keywords: phosphodiesterase inhibitor, inhibitor complex, hydrolase, zinc binding, magnesium binding
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: Q9Y233
• Total number of polymer chains: 2
• Total formula weight: 78873.80

Authors

Bartolome-Nebreda, J.M.,Conde-Ceide, S.,Delgado, F.,Martin, M.L.,Martinez-Viturro, C.M.,Pastor, J.,Tong, H.M.,Iturrino, L.,Macdonald, G.J.,Sanderson, W.,Megens, A.,Langlois, X.,Somers, M.,Vanhoof, G. (deposition date: 2012-09-28, release date: 2013-10-16, Last modification date: 2024-05-08)

Primary citation

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.
Discovery of a Potent, Selective and Orally Active Pde10A Inhibitor for the Potential Treatment of Schizophrenia.
J.Med.Chem., 57:4196-, 2014

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.

PubMed: 24758746
DOI: 10.1021/JM500073H

Experimental method

X-RAY DIFFRACTION (2.5 Å)