Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating arylsulfonamide groups.
Article Details
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Procopiou PA, Barrett VJ, Bevan NJ, Biggadike K, Butchers PR, Coe DM, Conroy R, Edney DD, Field RN, Ford AJ, Guntrip SB, Looker BE, McLay IM, Monteith MJ, Morrison VS, Mutch PJ, Richards SA, Sasse R, Smith CE
Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating arylsulfonamide groups.
J Med Chem. 2009 Apr 23;52(8):2280-8. doi: 10.1021/jm801016j.
- PubMed ID
- 19317397 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Isoprenaline Beta-1 adrenergic receptor EC 50 (nM) 7.94 N/A N/A Details Isoprenaline Beta-3 adrenergic receptor EC 50 (nM) 39.81 N/A N/A Details Salmeterol Beta-1 adrenergic receptor EC 50 (nM) 794.33 N/A N/A Details Salmeterol Beta-3 adrenergic receptor EC 50 (nM) 1258.93 N/A N/A Details