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Inhaled glucocorticoids used either alone or in combination with bronchodilators provides the foundation of current treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). This article describes our efforts to develop nonsteroidal glucocorticoid receptor (GR) modulators suitable for inhaled administration with improved efficacy and therapeutic margin compared to existing steroid-based drugs. Starting from high-throughput screening-derived GR antagonists, exemplified by the sulphonamide ( 9 ), a novel class of highly potent, indazole ether-based, GR modulators was discovered. The progress was highly dependent on the access to high-quality X-ray structures used to guide medicinal chemistry design. Two compounds, AZD5423 and AZD7594, were brought into clinical development for the inhaled treatment of asthma and COPD. |
