3 years ago

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

Identification
of a Potent, Highly Selective, and
Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate
Tracey Boyden, Jayvardhan Pandit, Patrick R. Verhoest, John F. Harms, Thomas A. Chappie, Laura McDowell, Mihaly Hajos, Nichole Vansell, John M. Humphrey, Adam Ogden, Dina McGinnis, William E. Hoffman, Robin J. Kleiman, Eric Arnold, Jiemin Lu, Rebecca E. O’Connor, Noha Maklad, Christopher J. Schmidt, Patricia A. Seymour, Che-Wah Lee, Edward X. Yang, Hirokazu Ueno, Zhijun Kang, Mary Piotrowski, Bethany L. Kormos, Christopher J. O’Donnell, Ethan Fisher, Cheng Chang, Christopher J. Helal
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b01466

DOI: 10.1021/acs.jmedchem.7b01466

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