title: Design and synthesis of long acting inhaled corticosteroids for the treatment of asthma.
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.
authors: Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. dave.millan@gmail.com
authors: David S
authors: DS
authors: Millan
authors: Stephen A
authors: SA
authors: Ballard
authors: Sara
authors: S
authors: Chunn
authors: Joseph A
authors: JA
authors: Dybowski
authors: Craig K
authors: CK
authors: Fulton
authors: Paul A
authors: PA
authors: Glossop
authors: Edouard
authors: E
authors: Guillabert
authors: Christopher A
authors: CA
authors: Hewson
authors: Rhys M
authors: RM
authors: Jones
authors: David J
authors: DJ
authors: Lamb
authors: Carolyn M
authors: CM
authors: Napier
authors: Toby A
authors: TA
authors: Payne-Cook
authors: Emmanuelle R
authors: ER
authors: Renery
authors: Matthew D
authors: MD
authors: Selby
authors: Michelle F
authors: MF
authors: Tutt
authors: Michael
authors: M
authors: Yeadon
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000627:therapeutic use; D000730:Androstadienes / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy* / Q000453:epidemiology / Q000503:physiopathology; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D058995:Dry Powder Inhalers; D000068298:Fluticasone; D022781:Hepatocytes; D006801:Humans; D008099:Liver; D008168:Lung; D008862:Microsomes, Liver; D009504:Neutrophils / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood
chemical_list: D000305:Adrenal Cortex Hormones; D000318:Adrenergic beta-Agonists; D000730:Androstadienes; D018927:Anti-Asthmatic Agents; D003692:Delayed-Action Preparations; D014409:Tumor Necrosis Factor-alpha; D000068298:Fluticasone