Abstract
A novel series of potent and selective sulfonamide derived β(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.
MeSH terms
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Administration, Inhalation
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Adrenergic beta-2 Receptor Agonists*
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Adrenergic beta-Agonists / chemical synthesis*
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Adrenergic beta-Agonists / pharmacokinetics
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Adrenergic beta-Agonists / pharmacology
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Animals
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Asthma / drug therapy*
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Benzeneacetamides / chemical synthesis*
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Benzeneacetamides / pharmacokinetics
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Benzeneacetamides / pharmacology
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Bronchoconstriction / drug effects
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CHO Cells
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Cricetinae
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Cricetulus
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Crystallography, X-Ray
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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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Liver / metabolism
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Male
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Models, Molecular
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Molecular Structure
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiopathology
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Pulmonary Disease, Chronic Obstructive / drug therapy*
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Rats
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Stereoisomerism
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Sulfonamides / chemical synthesis*
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology
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Trachea / drug effects
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Trachea / metabolism
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Trachea / physiopathology
Substances
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Adrenergic beta-2 Receptor Agonists
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Adrenergic beta-Agonists
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Benzeneacetamides
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Sulfonamides
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N-((4'-hydroxybiphenyl-3-yl)methyl)-2-(3-(2-((-2-hydroxy-2-(4-hydroxy-3-((methylsulfonyl)amino)phenyl)ethyl)amino)-2-methylpropyl)phenyl)acetamide