Discovery of a highly potent series of oxazole-based phosphodiesterase 4 inhibitors (original) (raw)
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Bioorganic & Medicinal Chemistry Letters, 2013
Abbreviations: CNS, central nervous system; cAMP, 3 0 ,5 0 -cyclic adenosine monophosphate; cGMP, 3 0 ,5 0 -cyclic guanosine monophosphate; PDE2, phosphodiesterase 2; PDE10, phosphodiesterase 10; SAR, structure-activity relationship.
Advances in the Development of Phosphodiesterase-4 Inhibitors
Journal of Medicinal Chemistry, 2020
Cyclic nucleotide phosphodiesterase 4 (PDE4) specifically hydrolyzes cyclic adenosine monophosphate (cAMP) and plays vital roles in biological processes such as cancer development. To date, PDE4 inhibitors have been widely studied as therapeutics for the treatment of various diseases such as chronic obstructive pulmonary disease, and many of them have progressed to clinical trials or have been approved as drugs. Herein, we review the advances in the development of PDE4 inhibitors in the past decade and will focus on their pharmacophores, PDE4 subfamily selectivity, and therapeutic potential. Hopefully, this analysis will lead to a strategy for development of novel therapeutics targeting PDE4.
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.
Quinazolines: Combined type 3 and 4 phosphodiesterase inhibitors
Bioorganic & Medicinal Chemistry Letters, 1998
A series of quinazolines has been prepared and evaluated for its ability to inhibit cyclic AMP phosphodiesterase type 3, type 4A, 4B and 4D. The most potent inhibitors showed IC50 values in the nanomolar range for type 3 and type 4 isoforms and bind with high affinity to the [3H]rolipram binding site. These quinazolines represent a new family of potent mixed PDE 3 / 4 inhibitors and are expected to have a therapeutic potential. 0 1998 Elsevier Science Ltd. All rights reserved. Isozyme selective phosphodiesterase (PDE) inhibitors may represent a new class of drugs for the treatment of obstructive pulmonary disease (e.g. asthma). PDE 3 inhibitors, and possibly PDE 4 inhibitors possess bronchodilator activity. On the other hand, synthesis and release of inflammatory mediators, chemotaxis and proliferation of inflammatory cells in response to antigen challenge are inhibited by agents that produce an increase in the intracellular concentration of cAMp.I3 Increase of cAMP level can be achieved by inhibition of cAMP PDE [3':5'-nucleotidohydrolase, EC 3.1.4.17]. Since the different isoenzymes, that preferentially hydrolyse cAMP, are not uniformly distributed in different cell types, 4'5 they are sensitive to selective inhibitors and are interesting drug targets for a variety of different diseases. The quest of novel antiinflammatory agents has led chemists and pharmacologists to focus on selective inhibitors of PDE 4 because it is the predominant form in human leukocytes. 13'5'6 The recent discovery of different cDNA isoforms and splice variants of PDE 4 suggests that the regulation of cAMP metabolism in leukocytes may be more complex than originally thought. Four distinct human isoforms, provisionally designated PDE 4A, 4B, 4C, 4D, 5 have been cloned and expressed. 7-1~ An increase in intracellular cAMP induces the synthesis of the A, B, and D isoforms, 6'12 suggesting a role for these enzymes in the long term regulation of cAMP metabolism. Mixed PDE 3 / 4 inhibitors may combine, therefore, both bronchodilator and antiinflammatory properties. Zardaverine [6-1 Fax
Bioorganic & Medicinal Chemistry Letters, 2002
The discovery, synthesis and biological activity of a series of triarylethane phosphodiesterase 4 inhibitors is described. Structure-activity relationship studies are presented for CDP840 (29), a potent, chiral, selective inhibitor of PDE 4 (IC 50 4 nM). CDP840 is non-emetic in the ferret at 30 mg kg À1 (po), active in models of inflammation and reverses ozone-induced bronchial hyperreactivity in the guinea pig. #
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.
Discovery of Phosphodiesterase-4 Inhibitors: Serendipity and Rational Drug Design
Australian Journal of Chemistry, 2014
Phosphodiesterase 4 (PDE4), the primary cyclic AMP-hydrolysing enzyme in cells, is a promising drug target for a wide range of mental disorders including Alzheimer's and Huntington's diseases, schizophrenia, and depression, plus a range of inflammatory diseases including chronic obstructive pulmonary disease, asthma, and rheumatoid arthritis. However, targeting PDE4 is complicated by the fact that the enzyme is encoded by four very closely related genes, together with 20 distinct isoforms as a result of mRNA splicing, and inhibition of some of these isoforms leads to intolerable side effects in clinical trials. With almost identical active sites between the isoforms, X-ray crystallography has played a critical role in the discovery and development of safer PDE4 inhibitors. Here we describe our discovery of a novel class of highly potent PDE4 via a 'virtuous' cycle of structure-based drug design and serendipity.
A series of phenyl alkyl ketone derivatives as inhibitors of phosphodiesterase 4 (PDE4) was subjected to 2D Quantitative Structure–Activity Relationships (2D QSAR) and Hologram Quantitative Structure–Activity Relationship (HQSAR) studies. Training and test sets were created by using K-means clustering on the original dataset. Stepwise linear regression analysis, replacement method and enhanced replacement methods were used for generating 2D QSAR models. The equation obtained thus were statistically significant and showed high correlation coefficient (R2=0.8374) and low standard deviation (S=0.4442). Different methods were used for validation of 2D QSAR models; robustness was confirmed with the help of leave one out cross validation (R2 cv=0.7189), Y scrambling (R2=0.3640), and by test set prediction (R2 pred=0.6867). A good correlation of topological, steric, electronic and electrotopological descriptors of phenyl alkyl ketone derivatives with the PDE4 inhibitory activity was recognized. HQSAR models were developed using different permutations of fragment size, hologram length and fragment type. The best HQSAR model showed an R2 value of 0.973 and R2 cv value of 0.641. The prediction on test set molecules was used to validate the HQSAR model. New molecules were designed based on the results of 2D QSAR and HQSAR studies and their activity was predicted using the developed models.
European Journal of Medicinal Chemistry, 2020
Ecto-nucleotide pyrophosphatases/ phosphodiesterases Thymidine 5 0-monophosphate paranitrophenyl ester Molecular docking studies a b s t r a c t Oxazole derivatives are important medicinal compounds which are inhibitors of various enzymes such as NPP1, NPP2, NPP3, tyrosine kinase, dipeptidyl-peptidase IV, cyclooxygenase-2, and protein tyrosine phosphatase. In this study, an extensive range of new biologically active biphenyl oxazole derivatives was synthesized in high to excellent yields (57e93%) through SuzukieMiyaura cross-coupling of bromophenyloxazole with different boronic acids. The reaction was carried out in wet toluene under mild conditions. Overexpression of nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) and NPP3 has been associated with various health disorders including chondrocalcinosis, cancer, osteoarthritis, and type 2 diabetes. We evaluated the inhibitory potential and selectivity of the synthesized compounds (3a-3q) towards NPP1 and NPP3 at 100 mM concentrations. We found two compounds that were selective and potent inhibitors of these two enzymes on the artificial substrate thymidine 5 0-monophosphate para-nitrophenyl ester: compound 3n inhibited NPP1 with an IC 50 of 0.15 mM, and compound 3f inhibited NPP3 with an IC 50 value of 0.17 mM. The compounds with promising inhibitory potential were docked inside the proteins of NPP1 and NPP3 isozymes to get insight into the plausible binding interactions with active site residues.
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.