PF 05180999 - CAS 1394033-54-5
Category: Inhibitor
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Molecular Weight:
Phosphodiesterase (PDE)
PF 05180999 is a potent and selective PDE2A inhibitor (IC50 = 1 nM), with 2000-fold selectivity for PDE2A over PDE10A. PF 05180999 was evaluated for schizophrenia and migraine, but no further development has been reported since 2014.
≥98% by HPLC
4-(1-Azetidinyl)-7-methyl-5-[1-methyl-5-[5-(trifluoromethyl)-2-pyridinyl]-1H-pyrazol-4-yl]-imidazo[5,1-f][1,2,4]triazine; PF05180999; PF-05180999; PF 5180999; PF5180999; PF-5180999; PF 5180999; PF999; PF-999; PF 999
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1.Inhibition of PDE2A, but not PDE9A, modulates presynaptic short-term plasticity measured by paired-pulse facilitation in the CA1 region of the hippocampus.
Fernández-Fernández D;Rosenbrock H;Kroker KS Synapse. 2015 Oct;69(10):484-96. doi: 10.1002/syn.21840. Epub 2015 Jul 29.
Phosphodiesterase (PDE) inhibitors are currently considered promising therapeutic targets for treatment of cognitive impairment in diseases such as Schizophrenia and Alzheimer's disease. Inhibitors of PDE2A and PDE9A have emerged as potential candidates shown to improve synaptic plasticity and memory function in animals. However, the functional relevance of their putative different localization in the neuron is not understood. Thus, this study aims at elucidating potential presynaptic effects of PDE2A inhibition in comparison to the inhibition of PDE9A. For this purpose, we used paired-pulse facilitation (PPF), a model of short-term synaptic plasticity related to presynaptic function. First, we performed a series of experiments to validate the model in acute rat hippocampal slices using several reference substances including calcium channel blockers, glutamatergic receptor antagonists, and GPCR agonists. Second, we analysed the effect of PDE2A and PDE9A inhibition and their role regulating the influence that the second messengers cAMP and cGMP exert on basal transmission. Our results show that the interplay between the adenylyl cyclase activator forskolin, the soluble guanylyl cyclase activator BAY 41-8543 and the PDE2A inhibitor PF-999 reveals a primarily presynaptic mechanism of action of PDE2A inhibition.
2.Identification of a Potent, Highly Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate.
Helal CJ;Arnold E;Boyden T;Chang C;Chappie TA;Fisher E;Hajos M;Harms JF;Hoffman WE;Humphrey JM;Pandit J;Kang Z;Kleiman RJ;Kormos BL;Lee CW;Lu J;Maklad N;McDowell L;McGinnis D;O'Connor RE;O'Donnell CJ;Ogden A;Piotrowski M;Schmidt CJ;Seymour PA;Ueno H;Vansell N;Verhoest PR;Yang EX J Med Chem. 2018 Feb 8;61(3):1001-1018. doi: 10.1021/acs.jmedchem.7b01466. Epub 2018 Jan 16.
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 (C;av,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.
3.Preclinical Evaluation of 18F-PF-05270430, a Novel PET Radioligand for the Phosphodiesterase 2A Enzyme.
Chen L;Nabulsi N;Naganawa M;Zasadny K;Skaddan MB;Zhang L;Najafzadeh S;Lin SF;Helal CJ;Boyden TL;Chang C;Ropchan J;Carson RE;Villalobos A;Huang Y J Nucl Med. 2016 Sep;57(9):1448-53. doi: 10.2967/jnumed.115.171454. Epub 2016 May 19.
The enzyme phosphodiesterase 2A (PF-05270430) is a potential target for development of novel therapeutic agents for the treatment of cognitive impairments. The goal of the present study was to evaluate the PDE2A ligand (18)F-PF-05270430, 4-(3-fluoroazetidin-1-yl)-7-methyl-5-(1-methyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)imidazo[1,5-f][1,2,4]triazine, in nonhuman primates.;METHODS: ;(18)F-PF-05270430 was radiolabeled by 2 methods via nucleophilic substitution of its tosylate precursor. Tissue metabolite analysis in rodents and PET imaging in nonhuman primates under baseline and blocking conditions were performed to determine the pharmacokinetic and binding characteristics of the new radioligand. Various kinetic modeling approaches were assessed to select the optimal method for analysis of imaging data.;RESULTS: ;(18)F-PF-05270430 was synthesized in greater than 98% radiochemical purity and high specific activity. In the nonhuman primate brain, uptake of (18)F-PF-05270430 was fast, with peak concentration (SUVs of 1.5-1.8 in rhesus monkeys) achieved within 7 min after injection. The rank order of uptake was striatum > neocortical regions > cerebellum. Regional time-activity curves were well fitted by the 2-tissue-compartment model and the multilinear analysis-1 (MA1) method to arrive at reliable estimates of regional distribution volume (VT) and binding potential (BPND) with 120 min of scan data.
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CAS 1394033-54-5 PF 05180999

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