Abstract
A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.
MeSH terms
-
2-Hydroxyphenethylamine / analogs & derivatives*
-
2-Hydroxyphenethylamine / chemical synthesis
-
2-Hydroxyphenethylamine / chemistry
-
2-Hydroxyphenethylamine / pharmacology
-
Administration, Oral
-
Adrenergic beta-2 Receptor Agonists*
-
Albuterol / analogs & derivatives
-
Albuterol / chemistry
-
Albuterol / pharmacology
-
Animals
-
Biological Availability
-
Bronchi / drug effects
-
Bronchi / physiology
-
CHO Cells
-
Cricetinae
-
Cricetulus
-
Cyclic AMP / biosynthesis
-
Dogs
-
Guinea Pigs
-
Humans
-
In Vitro Techniques
-
Microsomes / metabolism
-
Models, Molecular
-
Muscle Contraction / drug effects
-
Muscle, Smooth / drug effects
-
Muscle, Smooth / physiology
-
Rats
-
Salmeterol Xinafoate
-
Stereoisomerism
-
Structure-Activity Relationship
-
Sulfonamides / chemical synthesis*
-
Sulfonamides / chemistry
-
Sulfonamides / pharmacology
-
Trachea / drug effects
-
Trachea / physiology
Substances
-
3-(4-((6-((-2-hydroxy-2-(4-hydroxy-3-(hydroxymethyl)phenyl)ethyl)amino)hexyl)oxy)butyl)benzenesulfonamide
-
Adrenergic beta-2 Receptor Agonists
-
Sulfonamides
-
Salmeterol Xinafoate
-
2-Hydroxyphenethylamine
-
Cyclic AMP
-
Albuterol