PdCl 2 -catalyzed synthesis of a new class of isocoumarin derivatives containing aminosulfonyl / aminocarboxamide moiety: First identification of a isocoumarin based PDE4 inhibitor.
TL;DR: The isocoumarin 3u emerged as a new, safe and moderately selective PDE4B inhibitor could be useful for inflammatory diseases possibly including COVID-19.
About: This article is published in European Journal of Medicinal Chemistry.The article was published on 2021-10-05. It has received 12 citations till now. The article focuses on the topics: Isocoumarin & Isocoumarins.
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TL;DR: In this paper , a rapid synthesis of isocoumarins has been achieved via the Cu-catalysed cascade reaction involving tandem intramolecular cyclization followed by olefin addition under ultrasound irradiation.
4 citations
TL;DR: In this article, a new class of isoquinolin-1(2H)-ones derivatives containing an aminosulfonyl moiety were designed and explored as potential inhibitors of PDE4.
3 citations
TL;DR: In this paper, a Pd-catalysed regioselective synthesis of 4,5-disubstituted 7-membered N/O-heterocycles was achieved via the 7-endo-dig cyclization followed by C-C bond formation of 2-(1-alkynyl)phenylacetamide.
2 citations
TL;DR: In this paper , the sulphonic acid-functionalized Wang resin (Wang-OSO 3 H) was explored as a polymeric and recoverable acidic catalyst for the synthesis of isoindolo[2,1- a ]quinazoline-5,11-dione derivatives under green conditions.
1 citations
TL;DR: In this paper, the sulphonic acid-functionalized Wang resin (Wang-OSO3H) was explored as a polymeric and recoverable acidic catalyst for the synthesis of isoindolo[2,1-a]quinazoline-5,11-dione derivatives under green conditions.
1 citations
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TL;DR: A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation and is used to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
50,114 citations
TL;DR: The new SwissADME web tool is presented that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar are presented.
Abstract: To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.
6,135 citations
TL;DR: Seven co-crystal structures of PDE4 and bound inhibitors are presented that show the regulatory domain closed across the active site, thereby revealing the structural basis of Pde4 regulation, and small-molecule allosteric modulators are designed that do not completely inhibit enzymatic activity.
Abstract: Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I(max) approximately 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit.
350 citations
TL;DR: This review highlights the dialectical role of PDE4 in drug discovery and the disquisitive details of certain Pde4 inhibitors to provide an overview of the topics that still need to be addressed in the future.
Abstract: Phosphodiesterase-4 (PDE4), mainly present in immune cells, epithelial cells, and brain cells, manifests as an intracellular non-receptor enzyme that modulates inflammation and epithelial integrity. Inhibition of PDE4 is predicted to have diverse effects via the elevation of the level of cyclic adenosine monophosphate (cAMP) and the subsequent regulation of a wide array of genes and proteins. It has been identified that PDE4 is a promising therapeutic target for the treatment of diverse pulmonary, dermatological, and severe neurological diseases. Over the past decades, numerous PDE4 inhibitors have been designed and synthesized, among which roflumilast, apremilast, and crisaborole were approved for the treatment of inflammatory airway diseases, psoriatic arthritis, and atopic dermatitis, respectively. It is regrettable that the dramatic efficacies of a drug are often accompanied by adverse effects, such as nausea, emesis, and gastrointestinal reactions. However, substantial advances have been made to mitigate the adverse effects and obtain better benefit-to-risk ratio. This review highlights the dialectical role of PDE4 in drug discovery and the disquisitive details of certain PDE4 inhibitors to provide an overview of the topics that still need to be addressed in the future.
282 citations
TL;DR: This Article contains errors in Figure 5F–J, where the right-hand y axes ‘LncRNAs’ are incorrectly given as ‘Density (except lnc RNAs)’.
Abstract: Scientific Reports 6: Article number: 32753; published online: 08 September 2016; updated: 16 March 2017 This Article contains errors in Figure 5F–J, where the right-hand y axes ‘Density (lncRNAs)’ are incorrectly given as ‘Density (except lncRNAs)’. The correct Figure 5 appears below as Figure 1.
241 citations