Design and synthesis of long acting inhaled corticosteroids for the treatment of asthma |
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Authors: | Millan David S Ballard Stephen A Chunn Sara Dybowski Joseph A Fulton Craig K Glossop Paul A Guillabert Edouard Hewson Christopher A Jones Rhys M Lamb David J Napier Carolyn M Payne-Cook Toby A Renery Emmanuelle R Selby Matthew D Tutt Michelle F Yeadon Michael |
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Institution: | Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. dave.millan@gmail.com |
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Abstract: | 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. |
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Keywords: | Inhaled Corticosteroid Asthma |
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