2. Academic Validation
  3. Use of structure-based design to discover a potent, selective, in vivo active phosphodiesterase 10A inhibitor lead series for the treatment of schizophrenia

Use of structure-based design to discover a potent, selective, in vivo active phosphodiesterase 10A inhibitor lead series for the treatment of schizophrenia

  • J Med Chem. 2011 Jul 14;54(13):4536-47. doi: 10.1021/jm2001508.
Christopher J Helal 1,  Zhijun Kang,  Xinjun Hou,  Jayvardhan Pandit,  Thomas A Chappie,  John M Humphrey,  Eric S Marr,  Kimberly F Fennell,  Lois K Chenard,  Carol Fox,  Christopher J Schmidt,  Robert D Williams,  Douglas S Chapin,  Judith Siuciak,  Lorraine Lebel,  Frank Menniti,  Julia Cianfrogna,  Kari R Fonseca,  Frederick R Nelson,  Rebecca O'Connor,  Mary MacDougall,  Laura McDowell,  Spiros Liras
Affiliations

Affiliation

  • 1 Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States. [email protected]
PMID: 21650160 DOI: 10.1021/jm2001508
Abstract

Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability.

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