Synthesis, Structural Analysis, and Biological Evaluation of Thioxoquinazoline Derivatives as Phosphodiesterase 7 Inhibitors (original) (raw)
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Bioorganic & Medicinal Chemistry Letters, 2018
We describe the design, synthesis and evaluation of a series of N 2 ,N 4-diaminoquinazoline analogs as PDE5 inhibitors. Twenty compounds were prepared and these were assessed in terms of their PDE5 and PDE6 activity, ex-vivo vasodilation response, mammalian cytotoxicity and aqueous solubility. Molecular docking was used to determine the binding mode of the series and this was demonstrated to be consistent with the observed SAR. Compound 15 was the most active PDE5 inhibitor (IC 50 = 0.072 ± 0.008 µM) and exhibited 4.6-fold selectivity over PDE6. Ex-vivo assessment of 15 and 22 in a rat pulmonary artery vasodilation model demonstrated EC 50 s of 1.63 ± 0.72 µM and 2.28 ± 0.74 µM respectively.
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
Bioorganic & Medicinal Chemistry, 2008
Phosphodiesterase10A (PDE10A) is an important enzyme with diverse biological actions in intracellular signaling systems, making it an emerging target for diseases such as schizophrenia, Huntington's disease, and diabetes mellitus. The objective of the current 3D QSAR study is to uncover some of the structural parameters which govern PDE10A inhibitory activity over PDE3A/B. Thus, comparative molecular field analysis (CoMFA) and hologram quantitative structure-activity relationship (HQSAR) studies were carried out on recently reported 6,7-dimethoxy-4-pyrrolidylquinazoline derivatives as PDE10A inhibitors. The best CoMFA model using atom-fit alignment approach with the bound conformation of compound 21 as the template yielded the steric parameter as a major contributor (nearly 70%) to the observed variations in biological activity. The best CoMFA model produced statistically significant results, with the cross-validated ðr 2 cv Þ and conventional correlation ðr 2 ncv Þ coefficients being 0.557 and 0.991, respectively, for the 21 training set compounds. Validation of the model by external set of six compounds yielded a high (0.919) predictive value. The CoMFA models of PDE10A and PDE3A/B activity were compared in order to address the selectivity issue of these inhibitors. The best HQSAR model for PDE10A was obtained with an r 2 cv of 0.704 and r 2 ncv of 0.902 using atoms, bonds, connections, chirality, donor, and acceptor as fragment distinction and default fragment size of 4-7 with three components for the 21 compounds. The HQSAR model predicted the external test-set of compounds well since a good agreement between the experimental and predicted values was verified. Taken together, the present QSAR models were found to accurately predict the PDE10A inhibitory activity of the test-set compounds and to yield reliable clues for further optimization of the quinazoline derivatives in the dataset.
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.
Synthesis and evaluation of quinazoline derivatives as phosphodiesterase 7 inhibitors
Bioorganic & Medicinal Chemistry, 2013
The latest scientific findings concerning PDE7 and PDE4 inhibition suggest that selective small-molecule inhibitors of both enzymes could provide a novel approach to treat a variety of immunological diseases. In this context, we describe a new series of quinazoline derivatives from quinazolin-4-thiones which include a substituted biphenyl fragment. Some of these compounds show inhibitory potencies at submicromolar levels against the catalytic domain of PDE7.
Journal of Medicinal Chemistry, 2000
The synthesis of a new family of benzyl derivatives of 2,1,3-benzo-and benzothieno[3,2-a]thiadiazine 2,2-dioxides was achieved. The biological data revealed the first heterocyclic family of compounds with PDE 7 inhibitory properties appearing to be a new objective for the treatment of T-cell-dependent disorders. The IC 50 values or percent inhibition values of the compounds against PDE 7 were calculated by testing them against human recombinant PDE 7 expressed in S. cerevisiae. In this expression system the only cyclic nucleotide hydrolyzing activity present in cell extracts corresponded to human PDE 7. Isoenzyme selectivity PDE 7 versus PDE 4 and PDE 3 was also measured. Considering simultaneously inhibition of the three different isoenzymes, monobenzyl derivatives 15 and 23 showed interesting PDE 7 potency (around 10 µM); although not statistically significant, a trend toward selectivity with respect to PDE 3 and PDE 4 was obtained. Benzothiadiazine 16, although less potent at PDE 7 (IC 50 ) 25 µM), also showed a trend of selectivity toward PDE 3 and PDE 4. These compounds are considered the best leads for further optimization.
Phosphodiesterases (PDEs) are responsible for the hydrolysis of cyclic nucleotides (cAMP and c-GMP). Cyclic nucleotides are important intracellular secondary messengers in cell function, relaying the signals from hormones at specific cell-surface receptors. An increase of cAMP due to the stimulation of adenylyl cyclase or the inhibition of PDEs affects the activity of immune system and inflammatory cells. Thus, PDE4, a cAMP specific PDE, received much attention as a target for the treatment of the diseases like asthma and Chronic Obstructive Pulmonary Disease (COPD). Pyrazolo[4,3-c]quinoline-3-one nucleus has attracted considerable attention recently as PDE4 receptor antagonists which have shown remarkable therapeutic potential in the treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD). In the present study, three dimensional quantitative structure activity relationship (3D QSAR) approach using CoMFA and CoMSIA was applied to a series of 2, 5-dihydropyrazolo [4, 3-c] quinoline-3-ones as PDE4 receptor antagonists. For the purpose, 22 compounds from the series were used to develop and validate models. The robustness of the model was confirmed with the help of leave one out cross-validation method, while the predictive ability of models was tested using a test set containing three molecules. Novel compounds were designed on the basis of results of CoMFA and CoMSIA studies. Designed compounds were evaluated by Docking and Lipinski filters. 3D-QSAR models with high squared correlation coefficient of up to 0.9590 for CoMFA and 0.9740 for CoMSIA were established. Robustness of the models is demonstrated by R2cv values of up to 0.8600 and 0.8230 for CoMFA and CoMSIA, respectively. Predictive ability of the models is reflected by R2pred values of 0.865 and 0.926 for CoMFA and CoMSIA respectively. Predicted activity of the designed molecules correlated well with the docking scores and the molecules also passed the Lipinski filters. Developed models highlighted the importance of steric, electrostatic and hydrophobic properties of the molecules for PDE 4 receptor affinity. The designed compounds may serve as lead for the development of newer PDE4 inhibitors based on the 2, 5-dihydropyrazolo [4, 3-c] quinoline-3-one scaffold.
ACS Chemical Neuroscience, 2012
A neural network model has been developed to predict the inhibitory capacity of any chemical structure to be a phosphodiesterase 7 (PDE7) inhibitor, a new promising kind of drugs for the treatment of neurological disorders. The numerical definition of the structures was achieved using CODES program. Through the validation of this neural network model, a novel family of 5-imino-1,2,4-thiadiazoles (ITDZs) has been identified as inhibitors of PDE7. Experimental extensive biological studies have demonstrated the ability of ITDZs to inhibit PDE7 and to increase intracellular levels of cAMP. Among them, the derivative 15 showed a high in vitro potency with desirable pharmacokinetic profile (safe genotoxicity and blood brain barrier penetration). Administration of ITDZ 15 in an experimental autoimmune encephalomyelitis (EAE) mouse model results in a significant attenuation of clinical symptoms, showing the potential of ITDZs, especially compound 15, for the effective treatment of multiple sclerosis.
Discovery of benzo[d]imidazo[5,1-b]thiazole as a new class of phosphodiesterase 10A inhibitors
Bioorganic & Medicinal Chemistry Letters, 2013
The design, synthesis and structure activity relationship studies of a series of compounds from benzo[d]imidazo[5,1-b]thiazole scaffold as phosphodiesterase 10A (PDE10A) inhibitors are discussed. Several potent analogs with heteroaromatic substitutions (9a-d) were identified. The anticipated binding mode of these analogs was confirmed by performing the insilico docking experiments. Later, the heteroaromatics were substituted with saturated heteroalkyl groups which provided a tool compound 9e with excellent PDE10A activity, PDE selectivity, CNS penetrability and with favorable pharmacokinetic profile in rats. Furthermore, the compound 9e was shown to be efficacious in the MK-801 induced psychosis model and in the CAR model of psychosis.