fluticasone-propionate and Asthma

The discovery of a novel series of therapeutic agents that has been designed and optimized for treating chronic obstructive pulmonary disease is reported. The pharmacological strategy was based on the identification of compounds that inhibit a defined subset of kinase enzymes modulating inflammatory processes that would be effective against steroid refractory disease and exhibit a sustained duration of action after inhaled delivery.

Topics: Animals; Asthma; Dose-Response Relationship, Drug; Drug Discovery; Drug Resistance; Humans; Male; Mice; Mice, Inbred Strains; Molecular Structure; Protein Kinase Inhibitors; Protein Kinases; Pulmonary Disease, Chronic Obstructive; Steroids; Structure-Activity Relationship; U937 Cells

In this Letter we present data for a novel series of ICS for the treatment of asthma. 'Inhalation by design' principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Androstadienes; Animals; Anti-Asthmatic Agents; Asthma; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Drug Therapy, Combination; Dry Powder Inhalers; Fluticasone; Hepatocytes; Humans; Liver; Lung; Microsomes, Liver; Neutrophils; Randomized Controlled Trials as Topic; Rats; Tumor Necrosis Factor-alpha

A series of C-21 mercapto derivatives of hydrocortisone have been synthesized and evaluated in cell based transrepression and transactivation assays. The benzothiazole derivative, compound 6 not only showed a dissociated profile in vitro functional assays but also a pharmacological profile in a Brown-Norway rat therapeutic index model of asthma that dissociated side effects (thymolysis) while maintaining efficacy against pulmonary inflammation and lung function.

Topics: Administration, Inhalation; Animals; Asthma; Cell Line; Drug Discovery; Lung; Rats; Steroids; Structure-Activity Relationship; Sulfhydryl Compounds

The synthesis and anti-inflammatory potencies of a new class of 17beta-thioalkyl-16alpha,17alpha-ketal and -acetal androstanes are described. This new class of steroids was made by fragmentation of 2-thioxo-1,2-dihydropyrid-1-yl esters of the corresponding 17-acids to the 17-radical. The radical generated was trapped using a variety of radicophilic disulfides, giving a steroidal D-ring having acetal or ketal functionality at C-16 and C-17, together with a sulfide link at C-17. Compounds from this series bind to the glucocorticoid receptor with high potency and are functional agonists as measured by their ability to induce tyrosine aminotransferase activity in a rat hepatic cell line in vitro. These 17beta-thioalkyl androstanes potently inhibit Sephadex-induced rat lung inflammation when administered directly into the airways. The high topical potency, together with a low propensity to induce systemic glucocorticoid-like side effects (rat thymus involution), provides the present compounds with a high degree of airway selectivity compared with currently available inhaled glucocorticoids. The presently described 17beta-thioalkyl-16alpha,17alpha-ketal androstanes may be useful for therapies for inflammatory diseases such as asthma.

Topics: Androstanes; Animals; Asthma; Cell Line; Humans; Liver; Magnetic Resonance Spectroscopy; Male; Organ Size; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Structure-Activity Relationship; Thymus Gland; Tyrosine Transaminase