Design and synthesis of long acting inhaled corticosteroids for the treatment of asthma.

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Millan DS, Ballard SA, Chunn S, Dybowski JA, Fulton CK, Glossop PA, Guillabert E, Hewson CA, Jones RM, Lamb DJ, Napier CM, Payne-Cook TA, Renery ER, Selby MD, Tutt MF, Yeadon M

Design and synthesis of long acting inhaled corticosteroids for the treatment of asthma.

Bioorg Med Chem Lett. 2011 Oct 1;21(19):5826-30. doi: 10.1016/j.bmcl.2011.07.106. Epub 2011 Aug 11.

PubMed ID
21880489 [ View in PubMed
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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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
BudesonideGlucocorticoid receptorEC 50 (nM)12.4N/AN/ADetails
Fluticasone furoateGlucocorticoid receptorEC 50 (nM)0.49N/AN/ADetails
Fluticasone propionateGlucocorticoid receptorEC 50 (nM)1.09N/AN/ADetails