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.
MeSH terms
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Administration, Inhalation
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Animals
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Azetidines / chemical synthesis*
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Azetidines / chemistry
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Azetidines / pharmacology
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Bronchodilator Agents / chemical synthesis*
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Bronchodilator Agents / chemistry
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Bronchodilator Agents / pharmacology
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CHO Cells
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Cell Line
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Cell Membrane Permeability
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Cricetinae
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Cricetulus
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Diphenylacetic Acids / chemical synthesis*
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Diphenylacetic Acids / chemistry
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Diphenylacetic Acids / pharmacology
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Dogs
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Female
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Guinea Pigs
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Hepatocytes / metabolism
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Humans
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In Vitro Techniques
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Kinetics
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Male
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Microsomes, Liver / metabolism
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Muscle Relaxation / drug effects
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiology
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Pulmonary Disease, Chronic Obstructive / drug therapy*
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Radioligand Assay
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Rats
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Receptor, Muscarinic M3 / antagonists & inhibitors*
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Receptor, Muscarinic M3 / metabolism
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Stereoisomerism
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Structure-Activity Relationship
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Trachea / drug effects
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Trachea / physiology
Substances
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5-(3-(3-hydroxyphenoxy)azetidin-1-yl)-5-methyl-2,2-diphenylhexanamide
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Azetidines
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Bronchodilator Agents
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Diphenylacetic Acids
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Receptor, Muscarinic M3
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Recombinant Proteins