Identification of a Potent, Highly Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate

  • J Med Chem. 2018 Feb 8;61(3):1001-1018. doi: 10.1021/acs.jmedchem.7b01466.
Christopher J Helal  1 ,  Eric Arnold  1 ,  Tracey Boyden  1 ,  Cheng Chang  1 ,  Thomas A Chappie  2 ,  Ethan Fisher  1 ,  Mihaly Hajos  1 ,  John F Harms  2 ,  William E Hoffman  1 ,  John M Humphrey  1 ,  Jayvardhan Pandit  1 ,  Zhijun Kang  1 ,  Robin J Kleiman  1 ,  Bethany L Kormos  2 ,  Che-Wah Lee  1 ,  Jiemin Lu  1 ,  Noha Maklad  1 ,  Laura McDowell  1 ,  Dina McGinnis  1 ,  Rebecca E O'Connor  1 ,  Christopher J O'Donnell  1 ,  Adam Ogden  1 ,  Mary Piotrowski  1 ,  Christopher J Schmidt  2 ,  Patricia A Seymour  1 ,  Hirokazu Ueno  1 ,  Nichole Vansell  1 ,  Patrick R Verhoest  2 ,  Edward X Yang  1
Affiliations
  • 1. Pfizer Worldwide Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
  • 2. Pfizer Worldwide Research and Development , 1 Portland Street, Cambridge, Massachusetts 02139, United States.
PMID: 29293004 DOI: 10.1021/acs.jmedchem.7b01466
Abstract

Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor 1 with an imidazotriazine core to yield compounds of significantly enhanced potency. The analog PF-05180999 (30) was subsequently identified as a preclinical candidate targeting cognitive impairment associated with schizophrenia. Compound 30 demonstrated potent binding to PDE2A in brain tissue, dose responsive mouse brain cGMP increases, and reversal of N-methyl-d-aspartate (NMDA) antagonist-induced (MK-801, ketamine) effects in electrophysiology and working memory models in rats. Preclinical pharmacokinetics revealed unbound brain/unbound plasma levels approaching unity and good oral bioavailability resulting in an average concentration at steady state (Cav,ss) predicted human dose of 30 mg once daily (q.d.). Modeling of a modified release formulation suggested that 25 mg twice daily (b.i.d.) could maintain plasma levels of 30 at or above targeted efficacious plasma levels for 24 h, which became part of the human clinical plan.

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