Inhalation by design: novel tertiary amine muscarinic M(3) receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease.
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Glossop PA, Watson CA, Price DA, Bunnage ME, Middleton DS, Wood A, James K, Roberts D, Strang RS, Yeadon M, Perros-Huguet C, Clarke NP, Trevethick MA, Machin I, Stuart EF, Evans SM, Harrison AC, Fairman DA, Agoram B, Burrows JL, Feeder N, Fulton CK, Dillon BR, Entwistle DA, Spence FJ
Inhalation by design: novel tertiary amine muscarinic M(3) receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease.
J Med Chem. 2011 Oct 13;54(19):6888-904. doi: 10.1021/jm200884j. Epub 2011 Sep 20.
- PubMed ID
- 21870878 [ View in PubMed]
- Abstract
A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Tiotropium Muscarinic acetylcholine receptor M4 Protein Humans UnknownNot Available Details Tiotropium Muscarinic acetylcholine receptor M5 Protein Humans UnknownNot Available Details