A locally active antiinflammatory macrolide (MLD987) for inhalation therapy of asthma

Journal of Medicinal Chemistry
Rene HerspergerJohn R Fozard

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...Continue Reading

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Citations

Nov 23, 2011·European Journal of Clinical Pharmacology·P ZarogoulidisK Zarogoulidis
Jul 1, 2007·Expert Opinion on Drug Discovery·Peter Buchwald
Apr 9, 2008·The Journal of Allergy and Clinical Immunology·David J CousinsTak H Lee
Aug 6, 2005·Pharmacology & Therapeutics·Michelle M Epstein
Jun 28, 2011·Immunopharmacology and Immunotoxicology·Haeyong LeeYoosik Yoon
Aug 7, 2013·Journal of Pharmaceutical and Biomedical Analysis·Cynthia D SommersMichael T Boyne
Apr 17, 2017·Bioorganic & Medicinal Chemistry Letters·Mitchell NambuMitchell Mutz
Jul 1, 2005·Expert Review of Clinical Immunology·Fulvio BraidoGiorgio Walter Canonica

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