Discovery 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

  • J Med Chem. 2009 Aug 27;52(16):5188-96. doi: 10.1021/jm900521k.
Patrick R Verhoest  1 ,  Douglas S Chapin ,  Michael Corman ,  Kari Fonseca ,  John F Harms ,  Xinjun Hou ,  Eric S Marr ,  Frank S Menniti ,  Frederick Nelson ,  Rebecca O'Connor ,  Jayvardhan Pandit ,  Caroline Proulx-Lafrance ,  Anne W Schmidt ,  Christopher J Schmidt ,  Judith A Suiciak ,  Spiros Liras
Affiliations
  • 1. Neuroscience, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. [email protected]
PMID: 19630403 DOI: 10.1021/jm900521k
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.

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