Download MendeleyDiscovery of a Novel Class of Phosphodiesterase 10A Inhibitors and Identification of Clinical Candidate 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the Treatment of Schizophrenia
Verhoest, P.R., Chapin, D.S., Corman, M., Fonseca, K., Harms, J.F., Hou, X., Marr, E.S., Menniti, F.S., Nelson, F., O'Connor, R., Pandit, J., Proulx-Lafrance, C., Schmidt, A.W., Schmidt, C.J., Suiciak, J.A., Liras, S.(2009) J Med Chem 52: 5188-5196
- PubMed: 19630403
- DOI: https://doi.org/10.1021/jm900521k
- Primary Citation of Related Structures:
3HQW, 3HQY, 3HQZ, 3HR1 - PubMed Abstract:
By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique "selectivity pocket" for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.
Organizational Affiliation:
Neuroscience, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. patrick.r.verhoest@pfizer.com
