CHF6001 I: A Novel Highly Potent and Selective Phosphodiesterase 4 Inhibitor with Robust Anti-Inflammatory Activity and Suitable for Topical Pulmonary Administration (original) (raw)
Related papers
Journal of Pharmacology and Experimental Therapeutics, 2002
Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 351591) has been identified as a potent (IC 50 ϭ 58 nM) and highly selective type 4 phosphodiesterase (PDE4) inhibitor with oral bioactivity in several animal models of lung inflammation. N-(3,5-Dichloro-4pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 365351), the only significant in vivo metabolite, is also a potent and highly selective PDE4 inhibitor (IC 50 ϭ 20 nM). Both SCH 351591 and SCH 365351 inhibited cytokine production in human blood mononuclear cell preparations. Oral SCH 351591 significantly attenuated allergen-induced eosinophilia and airway hyperreactivity in allergic guinea pigs at doses as low as 1 mg/kg. In this model, oral SCH 365351 showed similar potency. When SCH 351591 was administered orally to allergic cynomolgus monkeys at 3 mg/kg, Ascaris suuminduced lung eosinophilia was blocked. Hyperventilation-induced bronchospasm in nonallergic guinea pigs, a model for exercise-induced asthma, was also suppressed significantly by oral SCH 351591 at 0.3 mg/kg. Cilomilast (SB 207499; Ariflo), a PDE4 inhibitor currently being developed for asthma and chronic obstructive pulmonary disease (COPD), was 10-to 30-fold less potent than SCH 351591 at inhibiting guinea pig lung eosinophilia and hyperventilation-induced bronchospasm. In a ferret model of emesis, maximum nonemetic oral doses of SCH 351591 and cilomilast were 5 and 1 mg/kg, respectively. Comparison of plasma levels at these nonemetic doses in ferrets to those at doses inhibiting hyperventilation-induced bronchospasm in guinea pigs gave a therapeutic ratio of 16 for SCH 351591 and 4 for cilomilast. Thus, SCH 351591 exhibits a promising preclinical profile as a treatment for asthma and COPD. Asthma is a complex multifactorial disease characterized by reversible airway obstruction, airway inflammation, and nonspecific airway hyperreactivity (Mayer and Wills-Karp, 1999; Bertrand, 2000). Chronic obstructive pulmonary diseases (COPDs), on the other hand, are characterized by mostly irreversible airway obstruction due to chronic bronchitis and emphysema (Hay, 2000). Inflammation of the airways is believed to be central to the airways dysfunction in asthma and COPD (O'Shaughnessy et al., 1997; Roche, 1998). In these conditions, the airway wall is infiltrated by a variety of inflammatory cells, including mast cells, macrophages, T lymphocytes, eosinophils, and neutrophils. These cells release a host of mediators, including cytokines, chemokines, and bronchospastic agents that act in concert with neurotransmitters such as acetylcholine and neurokinins from pulmonary nerves to produce bronchospasm, pulmonary edema, mucus hypersecretion, and other features of asthma and COPD. Eosinophilia is the dominant feature of lung inflammation in asthma, whereas COPD is marked by an intense pulmonary neutrophilia. Although bronchodilators such as -agonists and anticholinergics are widely used for symptomatic relief,
Journal of Pharmacology and Experimental Therapeutics, 2002
Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 351591) has been identified as a potent (IC 50 ϭ 58 nM) and highly selective type 4 phosphodiesterase (PDE4) inhibitor with oral bioactivity in several animal models of lung inflammation. N-(3,5-Dichloro-4pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 365351), the only significant in vivo metabolite, is also a potent and highly selective PDE4 inhibitor (IC 50 ϭ 20 nM). Both SCH 351591 and SCH 365351 inhibited cytokine production in human blood mononuclear cell preparations. Oral SCH 351591 significantly attenuated allergen-induced eosinophilia and airway hyperreactivity in allergic guinea pigs at doses as low as 1 mg/kg. In this model, oral SCH 365351 showed similar potency. When SCH 351591 was administered orally to allergic cynomolgus monkeys at 3 mg/kg, Ascaris suuminduced lung eosinophilia was blocked. Hyperventilation-induced bronchospasm in nonallergic guinea pigs, a model for exercise-induced asthma, was also suppressed significantly by oral SCH 351591 at 0.3 mg/kg. Cilomilast (SB 207499; Ariflo), a PDE4 inhibitor currently being developed for asthma and chronic obstructive pulmonary disease (COPD), was 10-to 30-fold less potent than SCH 351591 at inhibiting guinea pig lung eosinophilia and hyperventilation-induced bronchospasm. In a ferret model of emesis, maximum nonemetic oral doses of SCH 351591 and cilomilast were 5 and 1 mg/kg, respectively. Comparison of plasma levels at these nonemetic doses in ferrets to those at doses inhibiting hyperventilation-induced bronchospasm in guinea pigs gave a therapeutic ratio of 16 for SCH 351591 and 4 for cilomilast. Thus, SCH 351591 exhibits a promising preclinical profile as a treatment for asthma and COPD. Asthma is a complex multifactorial disease characterized by reversible airway obstruction, airway inflammation, and nonspecific airway hyperreactivity (Mayer and Wills-Karp, 1999; Bertrand, 2000). Chronic obstructive pulmonary diseases (COPDs), on the other hand, are characterized by mostly irreversible airway obstruction due to chronic bronchitis and emphysema (Hay, 2000). Inflammation of the airways is believed to be central to the airways dysfunction in asthma and COPD (O'Shaughnessy et al., 1997; Roche, 1998). In these conditions, the airway wall is infiltrated by a variety of inflammatory cells, including mast cells, macrophages, T lymphocytes, eosinophils, and neutrophils. These cells release a host of mediators, including cytokines, chemokines, and bronchospastic agents that act in concert with neurotransmitters such as acetylcholine and neurokinins from pulmonary nerves to produce bronchospasm, pulmonary edema, mucus hypersecretion, and other features of asthma and COPD. Eosinophilia is the dominant feature of lung inflammation in asthma, whereas COPD is marked by an intense pulmonary neutrophilia. Although bronchodilators such as -agonists and anticholinergics are widely used for symptomatic relief,
Current pharmaceutical design, 2017
Chronic respiratory diseases affect millions of people every day. According to World Health Organization estimates, ~235 million people suffer from asthma, ~64 million suffer from chronic obstructive pulmonary disease (COPD), and millions more suffer from allergic rhinitis around the world. In recent last years, the first phosphodiesterase 4 (PDE4) inhibitor, roflumilast, was approved as a treatment to reduce the risk of exacerbations in stable and severe COPD associated with chronic bronchitis and a history of exacerbations. PDE4 exists as four subtypes (A, B, C, and D) each with a capacity to degrade cAMP, a second messenger involved in inflammatory responses. PDE4 inhibitors inhibit PDE4 activity, consequently increasing cAMP levels. This results in an anti-inflammatory effect, improving lung function. Roflumilast is a selective and non-specific PDE4 inhibitor, with the potential to inhibit all PDE4 isoforms to some degree. Despite the pharmacological effects of roflumilast, its ...
Naunyn-Schmiedeberg's Archives of Pharmacology, 2002
Inhibitors of phosphodiesterase 4 (PDE4) possess bronchospasmolytic and anti-inflammatory properties, which make them very attractive drugs for the treatment of asthma and COPD. Unfortunately, many PDE4 inhibitors also produce central nervous and gastrointestinal side effects, which have limited their clinical application. PDE4 has two binding sites for the archetypal PDE4 inhibitor rolipram, and it has been suggested that binding to the high-affinity rolipram binding site (HARBS) is responsible for the side effects of PDE4 inhibitors. Recently, we have synthesised the PDE4 inhibitor CC3 which shows low affinity to the HARBS. In the present study we investigated the bronchospasmolytic and anti-inflammatory properties of this novel compound in comparison to rolipram and the PDE3 inhibitor motapizone. The airwayrelaxant properties of the PDE inhibitors were analysed in rat precision-cut lung slices (PCLS) in which airways were contracted by methacholine or in passively sensitised PCLS exposed to ovalbumin. The anti-inflammatory properties were investigated by measuring the release of TNF from endotoxin-treated human monocytes.
Pulmonary pharmacology & therapeutics, 2005
Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. Tumor necrosis factor alpha (TNF-alpha) plays a central role as a pro-inflammatory cytokine in COPD. TNF-alpha release is markedly inhibited by phosphodiesterase type 4 (PDE4) inhibitors that have proven efficacious in COPD clinical trials. The aim of this study was to compare the in vitro activities of the novel selective PDE4 inhibitors CI-1044 compared to well-known PDE4 inhibitors, rolipram and cilomilast, and to the glucocorticoid dexamethasone at reducing lipopolysaccharide (LPS)-induced TNF-alpha release in whole blood from COPD patients and healthy subjects. In the whole blood from COPD patients pre-incubation with PDE4 inhibitors or dexamethasone resulted in a dose-dependent inhibition of LPS-induced TNF-alpha release with IC(50) values of 1.3+/-0.7, 2.8+/-0.9 microM, higher to 10 microM and lesser than 0.03 microM for CI-104...
Phosphodiesterase 4 Inhibitors for the Treatment of COPD
Chest, 2002
Type 4 cyclic nucleotide phosphodiesterases (PDE4s) are metallo-hydrolases which specifically hydrolyze cAMP to AMP in various cells types. The catalytic core is a bimetallic ion center composed of a tightly bound Zn 2+ and a loosely bound Mg 2+ , which plays a dictating role in eliciting cAMP binding and catalysis activation. An invariant glutamine positioned opposite to the ion center serves as the substrate recognition determinant and synergizes the transient Mg-oxo-phosphate interaction in the substrate complex. The Mg 2+ binding is activated by a PKA-mediated serine phosphorylation and modulated through proteinprotein interactions, thus, providing efficient mechanisms in the temporal regulation of cAMP signaling. Several PDE4 inhibitors including roflumilast, cilomilast and rolipram also rely on the interaction with the glutamine and metallic ion center for binding, with their affinity enhanced dramatically by the presence of the Mg 2+ ion. Recent studies have provided new insights into the role of this enzyme in inflammatory settings, CFTR regulation, long term potentiation, and its importance in immune surveillance. The major inflammatory cytokines which are modulated with PDE4 inhibitors include TNFα, IL-2, IFNγ, IL-12, GM-CSF and LTB 4. The role of PDE4 inhibitors in modulating cytokines, lipid mediators and in mucociliary clearance, along with clinical efficacy in asthma and/or COPD demonstrated with roflumilast and cilomilast, suggest a broad antiinflammatory spectrum for these compounds. Presently, the major impediment to approval of these novel therapies has been the mechanism based gastrointestinal adverse events which has limited the dosing and the ultimate efficacy with these novel therapeutic agents.
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. #