Animal experiment:

Rats[1]Male Sprague-Dawley rats (weighing 250-320 g) under urethane anesthesia at 1.5 g/kg intraperitoneal (ip) are placed in a stereotaxic frame, where craniotomies are performed above the region of the medial prefrontal cortex (mPFC) and ipsilateral (CA)1/subiculum. Body temperature of the rat is maintained at 37℃ with an electrical heating pad. The femoral vein is cannulated for administration of test drugs (PF-05180999, etc.). After the conclusion of the experiments animals are euthanized with an iv bolus of urethane[1].

PF-05180999 is a phosphodiesterase 2A (PDE2A) inhibitor, with an IC50 of 1.6 nM.

PF-05180999 is a phosphodiesterase 2A (PDE2A) inhibitor, with an IC50 of 1.6 nM. PF-05180999 binds to the rat, dog and monkey PDE2A, with Kis of 4.2, 8.4, and 5.5 nM and IC50s of 2.6, 5.2, and 3.4 nM, respectively. PF-05180999 shows weak activity against PDE, with IC50s of 2.03 μM (PDE10A1), 26.969 μM (PDE7B), 50.09 μM (PDE11A4), and >56.25 μM (PDE1B1, PDE3A1, PDE4D3, PDE5A1, PDE6 (bovine), PDE8B, PDE9A1), respectively. PF-05180999 is also a weak inducer of CYP3A4, and with no direct inhibition of human recombinant cytochrome P450 (CYP) enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A) and no induction of CYP1A2[1].

PF-05180999 (Compound 30; 0.032-0.32 mg/kg mg/kg, s.c.) dramatically reduces the working memory errors produced by ketamine in a working memory radial arm maze (RAM) model in rats. PF-05180999 causes acute and exposure-dependent elevation in the accumulation of cGMP bulk levels in the cortex, striatum, and hippocampus, but with no changes in cAMP and the associated downstream phospho-cAMP response element-binding protein (p-CREB) in mice[1].

[1]. Helal CJ, et al. Identification of a Potent, Highly Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate. J Med Chem. 2018 Feb 8;61(3):1001-1018.