Discovery of a Novel Class of Phosphodiesterase 10A Inhibitors and Identification of Clinical Candidate 2-[4-(1-Methyl-4-pyridin-4-yl-1 H -pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the Treatment of Schizophrenia † † Coordinates of the PDE10A crystal structures have been deposited in... (original) (raw)
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Journal of Medicinal Chemistry, 2015
We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo[1,2-a]pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound 25a for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure− activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead 25a are described.
Phosphodiesterase 10 (PDE10) inhibitors: an updated patent review (2014-present)
Expert Opinion on Therapeutic Patents, 2019
Introduction: Phosphodiesterase 10 (PDE10) is one of at least 11 different PDE families, which are the enzymes that degrade adenosine 3′,5′-cyclic monophosphate (cAMP) and/or guanosine 3′,5′-cyclic monophosphate (cGMP) by hydrolyzing the phosphodiester bonds. Inhibition of PDE10A represents a molecular target in the treatment of conditions that would benefit from the increase of the level of cAMP and/or cGMP such as neurological and psychiatric disorders, cancer, and diabetes. Areas covered: The present article reviews the patent literature on PDE10A inhibitors (PDE10AIs) from 2014 to present and PDE10AI chemotypes from different chemical classes: heteroaryl-and aryl-nitrogen-heterocyclic compounds, unsaturated nitrogen-heterocyclic compounds with specific substituents such as pyrazolopyrimidine, aryloxymethyl cyclopropane, pyridizinone, imidazopyridine, triazoles and imidazo[2,1-a]isoidole. The article presents the potency of PDE10AIs, their efficacy in animal models, and their clinical utility in the treatment of schizophrenia. Therapeutic patents for the treatment of cancers, precancerous conditions, and diabetes were also collected. Expert opinion: Several potent PDE10AIs have been described so far; however, clinical trials have shown that without preclinical optimization, the benefit of PDE10AIs in the treatment of schizophrenia is confounded by a high placebo effect. Understanding of the requirements for PDE10AIs constitutes a challenging but promising field of drug discovery and development.
Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors
Bioorganic & Medicinal Chemistry Letters, 2011
Novel triazoloquinazolines have been found as phosphodiesterase 10A (PDE10A) inhibitors. Structureactivity studies improved the initial micromolar potency which was found in the lead compound by a 100-fold identifying 5-(1H-benzoimidazol-2-ylmethylsulfanyl)-2-methyl-[1,2,4]triazolo[1,5-c]quinazoline, 42 (PDE10A IC 50 = 12 nM) as the most potent compound from the series. Two X-ray structures revealed novel binding modes to the catalytic site of the PDE10A enzyme.
Journal of Pharmacology and Experimental Therapeutics, 2008
We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54 -59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374 -385, 2006; Neuropharmacology 51:386 -396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives
MedChemComm, 2014
PDE1 is a family of calcium-activated, dual substrate phosphodiesterases expressed in both the CNS and periphery that play a role in the integration of intracellular calcium and cyclic nucleotide signaling cascades. Exploration of the potential in targeting this family of enzymes to treat neuropsychiatric disorders has been hampered by a lack of potent, selective, and brain penetrable PDE1 inhibitors. To identify such compounds we used high-throughput screening, structure-based design, and targeted synthetic chemistry to discover the 4-aminoquinazoline 7a (PF-04471141) and the 4-indanylquinazoline 27 (PF-04822163) each of which are PDE1 inhibitors that readily cross the blood brain barrier. These quinazoline-based PDE1-selective inhibitors represent valuable new tools to study the biological processes regulated by PDE1 and to begin to determine the potential therapeutic utility of such compounds to treat neuropsychiatric disorders. † Electronic supplementary information (ESI) available: Broad panel ligand-receptor binding data, PDE1 assay data with standard error, select pharmacokinetic data for 7a and 27, X-ray crystal structure experimental information for 7a and 27, PDE1B1 enzyme purity data and binding assay protocol, and complete synthesis experimental details. The crystal structure of inhibitor 7a bound to the PDE10A catalytic subunit has been deposited to the RCSB protein data bank with the entry code 4NPV. See
Neuropharmacology, 2016
Schizophrenia symptoms are associated with alterations in basal ganglia-cortical networks that include the cyclic nucleotides (cAMP/cGMP) signaling pathways. Phosphodiesterase 10A (PDE10A) inhibitors have been considered as therapeutic agents for schizophrenia because the regulation of cAMP and cGMP in the striatum by PDE10A plays an important role in the signaling mechanisms of the striatal-cortical network, and thereby in cognitive function. In the present study we assessed in non-human primates (NHPs) the effects of a novel PDE10A inhibitor (FRM-6308) that has demonstrated high potency and selectivity for human recombinant PDE10A in vitro. The behavioral effects of FRM-6308 in a dose range were determined in rhesus monkeys using a standardized motor disability scale for primates, motor tasks, and the "drug effects on the nervous system" (DENS) scale. The neuronal metabolic effects of FRM-6308 were determined with [(18)F]-fluorodeoxyglucose PET imaging. Results showed that FRM-6308 did not have any specific effects on the motor system at s.c. doses up to 0.32 mg/kg in NHPs, which induced a significant increase in the FDG-SUV in striatum (F 16.069, p < 0.05) and cortical (F 15.181, p < 0.05) regions. Higher doses induced sedation and occasional involuntary movements with clear development of tolerance after repeated exposures. These findings suggest that FRM-6308 has the adequate pharmacological profile to advance testing in clinical trials and demonstrate antipsychotic efficacy of PDE10A inhibition for the treatment of schizophrenia patients.
Journal of medicinal chemistry, 2014
We report the identification of a PDE10A clinical candidate by optimizing potency and in vivo efficacy of promising keto-benzimidazole leads 1 and 2. Significant increase in biochemical potency was observed when the saturated rings on morpholine 1 and N-acetyl piperazine 2 were changed by a single atom to tetrahydropyran 3 and N-acetyl piperidine 5. A second single atom modification from pyrazines 3 and 5 to pyridines 4 and 6 improved the inhibitory activity of 4 but not 6. In the in vivo LC-MS/MS target occupancy (TO) study at 10 mg/kg, 3, 5, and 6 achieved 86-91% occupancy of PDE10A in the brain. Furthermore, both CNS TO and efficacy in PCP-LMA behavioral model were observed in a dose dependent manner. With superior in vivo TO, in vivo efficacy and in vivo PK profiles in multiple preclinical species, compound 5 (AMG 579) was advanced as our PDE10A clinical candidate.
Journal of Medicinal Chemistry, 2012
A new series of phosphodiesterase-9 (PDE9) inhibitors that contain a scaffold of 6-aminopyrazolopyrimidinone have been discovered by a combination of structure-based design and computational docking. This procedure significantly saved load of chemical synthesis and is an effective method for the discovery of inhibitors. The best compound 28 has an IC 50 of 21 nM and 3.3 µM respectively for PDE9 and PDE5, and about three orders of magnitude of selectivity against other PDE families. The crystal structure of the PDE9 catalytic domain in complex with 28 has been determined and shows a hydrogen bond between 28 and Tyr424. This hydrogen bond may account for the 860-fold selectivity of 28 against PDE1B, in comparison with about 30-fold selectivity of BAY73-6691. Thus, our studies suggest that Tyr424, a unique residue of PDE8 and PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors. The second messengers adenosine and guanosine 3',5'-cyclic monophosphate (cAMP and cGMP) modulate many physiological processes, such as cardiac and smooth muscle contraction, steroid hormone function, platelet aggregation, apoptosis, leukocyte migration, adrenal hyperplasia, inflammation, axon guidance and regeneration, memory, and circadian regulation. 1-6 Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze intracellular cAMP and cGMP and thus play key roles in the cellular processes. 7-10 Family-selective PDE inhibitors have been widely studied as therapeutics for treatment of human diseases. 11-17 The most successful example of this drug class is the PDE5 inhibitor sildenafil that has been marketed as drugs (Viagra & Revatio) for the treatments of male erectile dysfunction and pulmonary hypertension. 11,12