Inhaled glucocorticoids alone or in combination with bronchodilators are the mainstay of inhaled therapy for pulmonary diseases such as asthma or chronic obstructive pulmonary disease (COPD). Here we present the discovery of AZD7594, an inhaled second generation SGRM, which is currently being evaluated in a phase IIa study in asthma<sup>1)</sup>. With our first generation SGRM AZD5423 as starting point we describe how structure based design guided the extension of the indazole ether core to yield a novel subseries. The extension is utilising an induced reorientation of the ligand binding pocket of the receptor to access a new cavity which allows for polar interactions. As a beneficial outcome, the polar extension of the core structure improved solid state properties of the ligands. This new subset allowed for a full implementation of our inhalation drug design principles and delivered the candidate AZD7594. Similar as the predecessor AZD5423, AZD7594 combines excellent potency with fast systemic clearance but exhibits differentiated pharmacokinetics due to extended retention in lung tissue. Inhaled AZD7594 was shown to have a therapeutic advantage over fluticasone propionate, assessed as the ratio of the effects on lung edema and thymus weight in a rodent model of airway inflammation. In a modification of the same PD model, AZD7594 also exerted an enduring effect 42h after inhaled administration to demonstrate the potential for once daily treatment with an improved safety profile in patients.<br/>1) Study number D3741C00003

Discovery of AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator (SGRM) in clinical development for treatment of asthma

251st National Meeting (2016)

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