Phosphodiesterase inhibition has received much attention in the past 20years for the potential treatment of CNS disorders. A primary focus of this work is the enhancement of memory and/or cognitive ...functioning. The role of PDEs in the augmentation of cyclic nucleotide signaling makes these enzymes attractive targets for enhancing the effects of neuronal communication. This review focuses on recent findings with respect to the role of PDE2 inhibition in cognitive functioning. Special attention is paid to recently disclosed, selective tool compounds and the use of these tool compounds to support the role of PDE2 inhibition in cognition. Recently reported SAR and modeling work will be presented along with discussion of the entry of new PDE2 inhibitors into the clinic.
Phosphodiesterase inhibition has received much attention in the past 20years for the potential treatment of CNS disorders. A primary focus of this work is the enhancement of memory and/or cognitive functioning. The role of PDEs in the augmentation of cyclic nucleotide signaling makes these enzymes attractive targets for enhancing the effects of neuronal communication. This review focuses on recent findings with respect to the role of PDE2 inhibition in cognitive functioning. Special attention is paid to recently disclosed, selective tool compounds and the use of these tool compounds to support the role of PDE2 inhibition in cognition. Recently reported SAR and modeling work will be presented along with discussion of the entry of new PDE2 inhibitors into the clinic.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Inhibition of phosphodiesterase 2A (PDE2A) has been proposed as a potential approach to enhance cognitive functioning and memory through boosting intracellular cGMP/cAMP and enhancing neuroplasticity ...in memory-related neural circuitry. Previous preclinical studies demonstrated that PDE2A inhibitors could reverse
-methyl-D-aspartate receptor antagonist (5S,10R)-(+)-5-methyl-10,11-dihydro-5
-dibenzo
,
cyclohepten-5,10-imine or ketamine-induced memory deficit. Here, we report that the potent and selective PDE2A inhibitor 4-(1-azetidinyl)-7-methyl-5-1-methyl-5-5-(trifluoromethyl)-2-pyridinyl-1
-pyrazol-4-yl-imidazo5,1-
1,2,4triazine (PF-05180999) enhances long-term memory in a contextual fear conditioning model in the rat at the oral dose of 0.3 mg/kg. Target engagement at this efficacious dose was explored using in vivo autoradiography. Converse to the results of a decrease of PDE2A binding (target occupancy) by the PDE2A inhibitor, a paradoxical increase (up to 40%) in PDE2A binding was detected. However, a typical target occupancy curve could be generated by PF-05180999 at much higher doses. In vitro experiments using recombinant PDE2A protein or rat brain homogenate that contains native PDE2A protein demonstrated that increased cGMP after initial PDE2A inhibition could be responsible for the activation of PDE2A enzyme via allosteric binding to the GAF-B domain, leading to positive cooperativity of the dormant PDE2A enzymes. Our results suggest that when evaluating target engagement of PDE2A inhibitors for memory disorder in clinical setting with occupancy assays, the efficacious dose may not fall on the typical receptor/target curve. On the contrary, an increase in PDE2A tracer binding is likely seen. Our results also suggest that when evaluating target occupancy of enzymes, potential regulation of enzyme activities should be considered.
A series of potent and selective 1,2,4triazolo1,5-apyrimidine PDE2a inhibitors is reported. The design and improvement of the binding properties of this series was achieved using X-ray crystal ...structures in conjunction with careful analysis of electronic and structural requirements for the PDE2a enzyme. One of the lead compounds, compound 27 (DNS-8254), was identified as a potent and highly selective PDE2a enzyme inhibitor with favorable rat pharmacokinetic properties. Interestingly, the increased potency of compound 27 was facilitated by the formation of a halogen bond with the oxygen of Tyr827 present in the PDE2a active site. In vivo, compound 27 demonstrated significant memory enhancing effects in a rat model of novel object recognition. Taken together, these data suggest that compound 27 may be a useful tool to explore the pharmacology of selective PDE2a inhibition.
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A series of mechanism-based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with fused bicyclic diamine cores is described. In contrast to compounds built around a ...piperazine core, most of the fused bicyclic diamine bearing analogs prepared exhibited greater potency against rFAAH than the human enzyme. Several compounds equipotent against both species were identified and profiled in vivo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
High throughput screening using the recombinant human TRPV1 receptor was used to identify a series of pyridinylpiperazine ureas (3) as TRPV1 vanilloid receptor ligands. Exploration of the ...structure−activity relationships by parallel synthesis identified the essential pharmacophoric elements for antagonism that permitted further optimization via targeted synthesis to provide a potent orally bioavailable and selective TRPV1 modulator 41 active in several in vivo models.
The discovery of a series of novel, potent, and highly selective inhibitors of the DNA damage control kinase chk2 is disclosed. Here we report the first SAR study around inhibitors of this kinase. ...High-throughput screening of purified human chk2 led to the identification of a novel series of 2-arylbenzimidazole inhibitors of the kinase. Optimization was facilitated using homology models of chk2 and docking of inhibitors, leading to the highly potent 2-arylbenzimidazole 2h (IC50 15 nM). Compound 2h is an ATP-competitive inhibitor of chk2 that dose dependently protects human CD4+ and CD8+ T-cells from apoptosis due to ionizing radiation. This work suggests that a selective small molecule inhibitor of chk2 could be a useful adjuvant to radiotherapy, increasing the therapeutic window of such treatment.
In medicinal chemistry, accurate prediction of additivity-based structure–activity relationship (SAR) analysis rests on three assumptions: (1) a consistent binding pose of the central scaffold, (2) ...no interaction between the R group substituents, and (3) a relatively rigid binding pocket in which the R group substituents act independently. Previously, examples of nonadditive SAR have been documented in systems that deviate from the first two assumptions. Local protein structural change upon ligand binding, through induced fit or conformational selection, although a well-known phenomenon that invalidates the third assumption, has not been linked to nonadditive SAR conclusively. Here, for the first time, we present clear structural evidence that the formation of a hydrophobic pocket upon ligand binding in PDE2 catalytic site reduces the size of another distinct subpocket and contributes to strong nonadditive SAR between two otherwise distant R groups.
The nonselective cation channel TRPA1 (ANKTM1, p120) is a potential mediator of pain, and selective pharmacological modulation
of this channel may be analgesic. Although several TRPA1 activators ...exist, these tend to be either reactive or of low potency
and/or selectivity. The aim of the present study, therefore, was to identify novel TRPA1 agonists. Using a combination of
calcium fluorescent assays and whole-cell electrophysiology, we discovered several compounds that possess potent, selective
TRPA1-activating activity, including several lipid compounds (farnesyl thiosalicylic acid, farnesyl thioacetic acid, 15-deoxy-Î 12,14 -prostaglandin J 2 , and 5,8,11,14-eicosatetraynoic acid), and two marketed drugs: disulfiram (Antabuse; a compound used in the treatment of
alcohol abuse) and the antifungal agent chlordantoin. Farnesyl thiosalicylic acid activates the channel in excised patches
and in the absence of calcium. Furthermore, using a quadruple TRPA1 mutant, we show that the mechanism of action of farnesyl
thiosalicylic acid differs from that of the reactive electrophilic reagent allylisothiocyanate. As a TRPA1 agonist with a
potentially novel mechanism of action, farnesyl thiosalicylic acid may be useful in the study of TRPA1 channels.
Identification of some selective and potent HCN1 blockers is described.
The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is ...disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1-disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4-isopropylpiperazin-1-yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein.
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