Neil John Press

Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease

Phosphodiesterase (PDE)4, and to a lesser extent, PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for diseases including chronic obstructive pulmonary disease. Indeed, ibudilast and theophylline are utilized clinically, and roflumilast is in late‐stage clinical development. Unfortunately, however many PDE4 and dual PDE3/4 inhibitors have failed in early development due to low therapeutic ratios. The majority of these compounds are however orally administered and non‐selective for either PDE3(A, B) or PDE4(A, B, C, D) subtypes. Developing an inhaled dual PDE3/4 inhibitor with subtype specificity may represent one strategy to improve the therapeutic index. Indeed combined inhibition of PDE3 and PDE4 inhibitor has additive and synergistic anti‐inflammatory and bronchodilatory effects versus inhibition of either PDE3 or PDE4 alone. Given that synergy has been seen in terms of efficacy end points, an obvious concern is that synergy may also be observed in side effects. Interestingly, however, no synergy or additive effects with a combination of a PDE3 and PDE4 inhibitor in a cardiomyocyte assay were observed. This review will summarize the rationale for developing an inhaled dual PDE3/4 inhibitor, as a treatment for chronic obstructive pulmonary disease together with recent advances in trying to understand the pathogenesis of PDE inhibitor‐induced mesenteric vasculitis (a key potential dose‐limiting side effect of these agents), highlighting potential early and sensitive predictive biomarkers.

A common intracellular allosteric binding site for antagonists of the CXCR2 receptor

Background and purpose:u2002 We have previously shown that SB265610 (1‐(2‐bromo‐phenyl)‐3‐(7‐cyano‐3H‐benzotriazol‐4‐yl)‐urea) behaves as an allosteric, inverse agonist at the C‐X‐C chemokine (CXCR)2 receptor. The aim of this study was to determine whether SB265610, in addition to two other known antagonists, bind to either of the two putative, topographically distinct, allosteric binding sites previously reported in the Literature.

PDE4 Inhibitors : A Review of the Current Field

Publisher Summary nThis chapter focuses on phosphodiesterase-4 (PDE4) enzyme inhibitors and their potential therapeutic utility. The chapter presents the in vitro pharmacology of PDE4 inhibitors—focusing on human cells. PDE4 inhibition potently prevents the release of pro-inflammatory mediators from a range of cell types. PDE4 inhibitors have been shown to inhibit adhesion molecule expression, chemotaxis, proliferation, migration and differentiation, and the release of remodeling factors. The chapter discusses a method to reduce the impact of the side effects of PDE4 inhibition by limiting the delivery of the inhibitor only to the required site of action. In the chapter, some of these approaches have been described in the delivery of inhaled drugs for respiratory diseases, but the skin is another area suitable for local delivery. The addition of the anti-inflammatory properties of a PDE4 inhibitor would be expected to give long-term benefit in such readouts as exacerbation rate, changes in airway structure, and rate of decline of lung function. The addition of the anti-inflammatory properties of a PDE4 inhibitor would be expected to give long-term benefit in such readouts as exacerbation rate, changes in airway structure, and the rate of decline of lung function.

An inhibitor of NADPH oxidase-4 attenuates established pulmonary fibrosis in a rodent disease model.

Idiopathic pulmonary fibrosis is a chronic progressive disease of increasing prevalence for which there is no effective therapy. Increased oxidative stress associated with an oxidant-antioxidant imbalance is thought to contribute to disease progression. NADPH oxidases (Nox) are a primary source of reactive oxygen species within the lung and cardiovascular system. We demonstrate that the Nox4 isoform is up-regulated in the lungs of patients with IPF and in a rodent model of bleomycin-induced pulmonary fibrosis and vascular remodeling. Nox4 is constitutively active, and therefore increased expression levels are likely to contribute to disease pathology. Using a small molecule Nox4/Nox1 inhibitor, we demonstrate that targeting Nox4 results in attenuation of an established fibrotic response, with reductions in gene transcripts for the extracellular matrix components collagen 1α1, collagen 3α1, and fibronectin and in principle pathway components associated with pulmonary fibrosis and hypoxia-mediated vascular remodeling: transforming growth factor (TGF)-β1, plasminogen activator inhibitor-1, hypoxia-inducible factor, and Nox4. TGF-β1 is a principle fibrotic mediator responsible for inducing up-regulation of profibrotic pathways associated with disease pathology. Using normal human lung-derived primary fibroblasts, we demonstrate that inhibition of Nox4 activity using a small molecule antagonist attenuates TGF-β1-mediated up-regulation in expression of profibrotic genes and inhibits the differentiation of fibroblast to myofibroblasts, that is associated with up-regulation in smooth muscle actin and acquisition of a contractile phenotype. These studies support the view that targeting Nox4 may provide a therapeutic approach for attenuating pulmonary fibrosis.

Therapeutic potential of adenosine receptor antagonists and agonists

The adenosine receptors (A1, A2A, A2B and A3) are important and ubiquitous mediators of cellular signalling, which play vital roles in protecting tissues and organs from damage. Launched drugs include the adenosine receptor antagonists theophylline and doxofylline (both used as bronchodilators in respiratory disorders such as asthma), while several compounds are presently in clinical trials for a range of indications, including heart failure, Parkinsons disease, rheumatoid arthritis, cancer, pain and chronic obstructive pulmonary disease. A host of companies and institutions are addressing the huge potential for the development of selective adenosine receptor agonists and antagonists, so that it appears we are on the verge of a new wave of compounds approaching the market for many unmet medical needs. This review presents an analysis of the patenting activity in the area for 2006 and an interpretation and reflection on the developments that we can expect in the future.

The total synthesis of alkaloids (–)-histrionicotoxin 259A, 285C and 285EAll new compounds exhibited satisfactory spectroscopic and analytical and/or exact mass data. Electronic supplementary information (ESI) available: experimental procedures for the preparation of compounds 4, 5, 13, 16, 22 and 25. See http://www.rsc.org/suppdata/cc/b1/b111514f/

The first total syntheses of three unsymmetrical (i.e. different terminal groups in the side chains) members of the histrionicotoxin family of alkaloids have been accomplished via stepwise introduction of the two side chain moieties onto a common tricyclic core.

CGH2466, a combined adenosine receptor antagonist, p38 mitogen-activated protein kinase and phosphodiesterase type 4 inhibitor with potent in vitro and in vivo anti-inflammatory activities

1 Theophylline, a phosphodiesterase inhibitor and adenosine receptor antagonist, is used in asthma and chronic obstructive pulmonary disease (COPD) treatment. However, the relatively low effectiveness of theophylline have recently led to reduced usage. The goal of the present study was to identify a theophylline‐like compound with improved effectiveness. 2 We discovered CGH2466, which not only antagonised the adenosine A1, A2b and A3 receptors with IC50 values of 19±4, 21±3 and 80±14u2003nM, respectively, but also inhibited the p38 mitogen‐activated protein (MAP) kinases α and β and the phosphodiesterase 4D (PDE4D) isoenzyme with IC50 values of 187±18, 400±38 and 22±5u2003nM, respectively. 3 Despite similar potencies on individual targets, CGH2466 inhibited the production of cytokines and oxygen radicals by human peripheral blood leucocytes in vitro, more potently (IC50 values between 30 and 50u2003nM) than the standard p38 MAP kinase inhibitor SB203580 (30u2003nM to >1u2003μM), the PDE4 inhibitor cilomilast (120–400u2003nM) and the broad spectrum adenosine receptor antagonist CGS15943 (>10u2003μM). 4 When given either orally or locally into the lungs, CGH2466 (3 to 10u2003mgu2003kg−1) inhibited the ovalbumin‐ or lipopolysaccharide‐induced airway inflammation in mice more potently than the single receptor antagonists or enzyme inhibitors used alone. 5 In conclusion, CGH2466 through its combined activities at multiple targets exerted a powerful anti‐inflammatory effect and therefore may have beneficial therapeutic value in diseases such as asthma and COPD.

Targeting the serotonin pathway for the treatment of pulmonary arterial hypertension

As we uncover the complex pathophysiology underlying idiopathic and familial pulmonary arterial hypertension, multiple disease associated pathways, cell types and processes reveal links to elements of the serotonin system. Beyond the original serotonin hypothesis observed with anorexigens, and the latterly demonstrated association with vascular tone and pulmonary artery smooth muscle cell proliferation, recent studies suggest links to BMPR2, PDGF and RhoK pathways, as well as an impact upon more complex lesion formation and pathologic bone marrow progenitor mobilization. Clinical experience with antagonists targeting the various elements of the serotonin pathway has been unsatisfactory, yet perhaps this is less than surprising given our expanding knowledge around serotonin production and signaling biology, which indicate opportunities for novel therapeutic options.

Microwave-mediated synthesis of an arylboronate library

A series of arylboronates has been synthesized from the reaction of 2-(2-, (3-, or (4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1{1-3} respectively with a range of N-, S-, and O-nucleophiles, using microwave-mediated chemistry. For the synthesis of N- and S-substituted boronates, a supported base, PS-NMM, was employed, and many reactions were complete within 15 min. With O-nucleophiles, a mixture of tetrabutylammonium bromide, potassium carbonate, and sodium hydroxide was employed. The resulting aminomethyl, mercaptomethyl, or alkoxy-/phenoxymethyl-arylboronates were subjected to microwave-mediated Suzuki Miyaura coupling reactions to afford a range of biaryls in moderate to good yields. The X-ray structures of five boronates were determined.

New Highly Potent and Selective Adenosine A3 Receptor Antagonists

A class of potent, selective adenosine A(3) receptor antagonists was obtained via optimisation of the screening hit N-[4-(4-methoxyphenyl)-thiazol-2-yl]-acetamide. Structural modifications of this hit revealed very quickly that a 5-(pyridin-4-yl) substituent on the 2-aminothiazole ring was optimal for high potency at the adenosine A(3) receptor. Structure activity relationship studies led to both potent and selective A(3) receptor antagonists, including N-[5-pyridin-4-yl-4-(3,4,5-trimethoxyphenyl)-thiazol-2-yl]-acetamide, a highly potent aden-osine A(3) receptor antagonist with greater than 100- fold selectivity against the related adenosine receptors. As well as demonstrating selective in vitro binding on the human A(3) adenosine receptor, this compound was also shown to selectively block the rat A(3) receptor in vivo. This important new compound can be readily synthesised in four steps from commercially available starting materials.