pf-05180999

Description: PF-05180999 is a phosphodiesterase 2A (PDE2A) inhibitor, with an IC50 of 1.6 nM. PF-05180999 was identified as a preclinical candidate targeting cognitive impairment associated with schizophrenia. PF-05180999 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 PF-05180999 at or above targeted efficacious plasma levels for 24 h, which became part of the human clinical plan.

References: J Med Chem. 2018 Feb 8; 61(3):1001-1018.