Discovery of a Novel Class of Phosphodiesterase 10A Inhibitors and Identification of Clinical Candidate 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the Treatment of Schizophrenia†Coordinates of the PDE10A crystal structures have been deposited in the Protein Data Bank for compound 1 (3HQW), 2 (3HQY), 3 (3HQW) and 9 (3HR1).

Abstract

By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique "selectivity pocket" for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

“…In fact, most of cAMP-positive cells were co-stained with the antisubstance P antibody in the rat striatum (Figure 4a). Both TAK-063 and MP-10 bind to the substrate-binding site in the catalytic domain of PDE10A (Kunitomo et al, 2014;Verhoest et al, 2009); thus, increased cAMP and cGMP by PDE10A inhibition and/or dopamine increase could compete with TAK-063 and MP-10 at this domain. In general, faster offrate enzyme inhibitors are more sensitive than slower offrate inhibitors to binding inhibition by enzyme substrates.…”

“…Compound 1 was referred to as compound 19e in Yoshikawa et al (2015). MP-10 has been reported as a potent and selective PDE10A inhibitor developed by Pfizer, Inc. (Grauer et al, 2009;Verhoest et al, 2009). [ 3 H]T-773 (37.0 MBq/ml in ethanol; specific radioactivity = 555 GBq/mmol; radiochemical purity = 99.9%) was synthesized by Quotient Bioresearch (Radiochemicals) Ltd (Cambridgeshire, UK).…”

“…Both TAK-063 and MP-10 bind to the substrate-binding site in the catalytic domain of PDE10A (Kunitomo et al, 2014;Verhoest et al, 2009); thus, cAMP and cGMP levels increased by PDE10A inhibition and/or (e) Activation of MSNs by compound 1. mRNA levels of substance P (SP) and enkephalin (Enk) in the rat striatum were measured by quantitative PCR 3 h after administration of compound 1. Data are presented as mean+SEM (n = 6).…”

Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors

“…In this experiment, MP-10 (2.5 mg/kg s.c.), 16 a potent and selective PDE10 inhibitor was predosed since it was found to greatly increase the signal-to-noise ratio of the tracer. This can be explained by the fact that PDE10 inhibition increases intracellular cGMP, which is known to activate PDE2 through its GAF domain.…”

Synthesis and <i>in Vivo</i> Evaluation of Novel Quinoline Derivatives as Phosphodiesterase 10A Inhibitors

“…9) Further, some selective PDE10A inhibitors have shown potent efficacy in several rodent behavioral models of schizophrenia. [10][11][12][13][14] PDE10A inhibitors have therefore garnered attention as a new therapeutic approach for the treatment of schizophrenia. [15][16][17][18][19][20][21][22][23][24][25] Among reported PDE10A inhibitors, TP-10 and MP-10 ( Fig.…”