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Phosphodiesterases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Moritz Helmstädter, Manfred Schubert-Zsilavecz
It was noticed that PDE4 isoforms have a high level of expression in cells that regulate inflammatory responses and tissue remodelling such as most immune cells including macrophages, neutrophils, eosinophils and lymphocytes (Torphy, 1998; Korhonen et al., 2013). Early PDE4-selective inhibitors such as rolipram showed potent cAMP-mediated anti-inflammatory effects both in cellular and animal models which motivated pharmaceutical companies to invest a lot in developing PDE inhibitors for inflammation-related diseases such as asthma, COPD, allergic rhinitis and idiopathic pulmonary fibrosis. Experiments with carrageenan-induced paw inflammations show that rolipram increases the expression of mitogen-activated protein kinase phosphatase 1 (MKP-1). Additionally PDE4-Inhibitors suppress a variety of inflammatory responses including proliferation, chemotaxis, phagocytosis and release of pro-inflammatory mediators (Raker et al., 2016). Increased intracellular cAMP attenuates the expression of pro-inflammatory cytokines such as tumour necrosis factor alpha and leads to a higher production of anti-inflammatory cytokines such as interleukin-10. It also suppresses the expression of chemokines such as macrophage inflammatory protein 1a and 1b and suppresses the expression of pro-inflammatory lipid mediator leukotriene B4 (Serezani et al., 2008).
Site-Specific Antibody Conjugation for ADC and Beyond
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
The site-specific antibody conjugation has been applied for preparing immunoconjugates against other diseases such as autoimmune diseases and atherosclerosis. A highly potent phosphodiesterase 4 (PDE4) inhibitor, GSK256066, was site-specifically coupled to a human anti-CD11a through an unnatural amino acid, pAcF, introduced at HC-A122 with DAR at ~2 [69]. PDE4 is a cAMP phosphodiesterase widely expressed in a variety of cells and some small molecule PDE4 inhibitors showed wide-ranging preclinical efficacy in autoimmune diseases with a few being approved by regulatory agencies for the treatment of some moderate to severe inflammatory conditions. However, dose-limiting side effects have impeded their broader therapeutic application. The site-specific conjugation of pan-immune cell targeting human anti-CD11a with GSK256066 resulted in an immunoconjugate that was rapidly internalized into immune cells and suppressed lipopolysaccharide (LPS)-induced TNFa secretion in primary human monocytes. In another study, a liver X receptor (LXR) agonist was site-specifically conjugated to pAcF at HC-A122 of anti-CD11a [70]. Liver X receptor agonists have been explored as potential treatments for atherosclerosis and other diseases based on their ability to induce reverse cholesterol transport and suppress inflammation. However, this therapeutic potential has been limited by on-target adverse effects in the liver mediated by excessive lipogenesis after the interaction of the ligand with LXR-a. To prevent the adverse effect, the aminoooxy-modified LXR agonist was coupled to pAcF in anti-CD11a for selective delivery of the agonist to monocytes/macrophages while sparing hepatocytes. The anti-CD11a IgG-LXR agonist immunoconjugate induced LXR activation specifically in human THP-1 monocyte/macrophage cells in vitro with EC50 at nM range, but had no significant effect in hepatocytes, indicating that the payload delivery was CD11a-mediated. This approach represents a fundamentally different strategy that uses tissue targeting to overcome the limitations of LXR agonists for potential use in treating atherosclerosis.
Regioselective formation of new 3-S-alkylated-1,2,4-triazole-quinolones
Published in Journal of Sulfur Chemistry, 2022
Ashraf A. Aly, Mohamed Abd El-Aziz, Yaseen A.M.M. Elshaier, Alan B. Brown, Hazem M. Fathy, Stefan Bräse, Martin Nieger, Mohamed Ramadan
Interestingly, quinoline-based molecules have shown anti-inflammatory activity targeting several pharmacological targets such as Phosphodiesterase 4 (PDE4), Transient Receptor Potential Vanilloid 1 (TRPV1), TNF-α converting enzyme (TACE) and Cyclooxygenase (COX). Structure Activity Relationship (SAR) of quinolones have been used to study the mechanism of the pharmacological activities of quinolines [6].