A Locally Active Antiinflammatory Macrolide (MLD987) for Inhalation Therapy of Asthma

Abstract

One of the characteristic features of asthma is a persistent pulmonary inflammation, with increased numbers of eosinophils and activated T-lymphocytes in the airways. T-helper cells of the Th2 phenotype play a pivotal role in the pathogenesis of asthma, and they are believed to orchestrate the asthmatic response by releasing a wide repertoire of cytokines. Herein, we describe the design, synthesis, and evaluation in models of allergic asthma of a locally active T-cell modulator, MLD987 (1). Compound 1 is a potent immunosuppressant that inhibits the activation, proliferation, and release of cytokines from T-cells with IC(50) values in the low nanomolar range. In a Brown-Norway rat model of allergic asthma, 1, when given into the airways by intratracheal administration (ED(50) = 1 mg/kg) or by inhalation (ED(50) = 0.4 mg/kg), potently reduced the influx of leukocytes into bronchoalveolar lavage fluid samples obtained from antigen-challenged animals. In contrast, 1 had an appreciably weaker activity in this model when given orally or intravenously. Pharmacokinetic evaluation in rat and rhesus monkey showed that 1 had both a low oral (2-4%) and a low pulmonary (7%, monkey) bioavailability. These findings are consistent with a local site of action of the compound and rule out that its antiinflammatory activity in the lung was caused by systemically absorbed material, which had been swallowed during inhalation or which had entered the circulation via the airways. Local administration and the metabolically soft structure of 1, which favors rapid systemic metabolism to less immunosuppressive metabolite 2, are the main reasons for the low exposure and weak systemic activity of the compound. Administration of a locally active compound such as 1, by inhalation, should reduce systemic side effects. Our results indicate that 1 has the potential to serve as an alternative to inhaled glucocorticosteroids for the long-term therapy of asthma of all grades of severity.

Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases

“…MLD987 is a potent immunosuppressant that inhibits the activation, proliferation and release of cytokines from T-cells with IC (50) values in the low nanomolar range. Inhaled administration reduced systemic side effects, lending support to the view that MLD987 has the potential to serve as an alternative to inhaled glucocorticosteroids for the long-term therapy of asthma [180]. Finally, there is in vitro experience that macrolides could induce bronchodilation [43].…”

“…Add-on inhaled AZM administration has proved successful in improving local bacterial control by means of anti-inflammatory and immunomodulatory effects [150]. Hersperger et al [180] administered MLD987 based on the concept that T-helper cells of the Th2 phenotype are of paramount importance in the pathogenesis of asthma through numerous cytokines. A locally active T-cell modulator, MLD987, was given by inhalation, orally or intravenously.…”

Therapeutic approaches for control of transcription factors in allergic disease

“…48,49 A locally active derivative of these drugs (MLD987) has recently been developed for inhalation treatment in asthma. 50 Studies in animal models suggest that this molecule might suppress T H 2-mediated inflammation without the negative systemic side effects seen with CsA, such as nephrotoxicity and hepatotoxicity. It will be interesting to see how this molecule performs in clinical trials.…”

Retrometabolism‐Based Drug Design and Targeting

“…Hence, this approach may yield useful SD analogs of cyclosporine with considerable therapeutic potential for local activity with minimal systemic side effects. Soft Tacrolimus Analogs Along the same conceptual lines as for cyclosporine, a soft analog of tacrolimus (FK506; PrografÔ, 144), another widely used calcineurin inhibitor, has also been explored as a potential candidate for the inhalation therapy of asthma [353]. The corresponding carboxylic ester incorporating compound, MLD987 (145) (Fig.…”