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

David S Millan; Stephen A Ballard; Sara Chunn; Joseph A Dybowski; Craig K Fulton; Paul A Glossop; Edouard Guillabert; Christopher A Hewson; Rhys M Jones; David J Lamb; Carolyn M Napier; Toby A Payne-Cook; Emmanuelle R Renery; Matthew D Selby; Michelle F Tutt; Michael Yeadon

doi:10.1016/j.bmcl.2011.07.106

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.

Authors

David S Millan¹, Stephen A Ballard, Sara Chunn, Joseph A Dybowski, Craig K Fulton, Paul A Glossop, Edouard Guillabert, Christopher A Hewson, Rhys M Jones, David J Lamb, Carolyn M Napier, Toby A Payne-Cook, Emmanuelle R Renery, Matthew D Selby, Michelle F Tutt, Michael Yeadon

Affiliation

¹ Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. dave.millan@gmail.com

PMID: 21880489
DOI: 10.1016/j.bmcl.2011.07.106

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.

MeSH terms

Administration, Inhalation
Adrenal Cortex Hormones / administration & dosage
Adrenal Cortex Hormones / chemical synthesis*
Adrenal Cortex Hormones / pharmacokinetics*
Adrenal Cortex Hormones / pharmacology
Adrenergic beta-Agonists / administration & dosage
Adrenergic beta-Agonists / therapeutic use
Androstadienes / chemistry
Androstadienes / pharmacology
Animals
Anti-Asthmatic Agents / administration & dosage
Anti-Asthmatic Agents / chemical synthesis*
Anti-Asthmatic Agents / pharmacokinetics*
Anti-Asthmatic Agents / pharmacology
Asthma / drug therapy*
Asthma / epidemiology
Asthma / physiopathology
Delayed-Action Preparations
Dose-Response Relationship, Drug
Drug Design*
Drug Evaluation, Preclinical
Drug Therapy, Combination
Dry Powder Inhalers
Fluticasone
Hepatocytes
Humans
Liver
Lung
Microsomes, Liver
Neutrophils / metabolism
Randomized Controlled Trials as Topic
Rats
Tumor Necrosis Factor-alpha / biosynthesis
Tumor Necrosis Factor-alpha / blood

Substances

Adrenal Cortex Hormones
Adrenergic beta-Agonists
Androstadienes
Anti-Asthmatic Agents
Delayed-Action Preparations
Tumor Necrosis Factor-alpha
Fluticasone