Synthesis and Structure−Activity Relationships of Long-acting β2 Adrenergic Receptor Agonists Incorporating Arylsulfonamide Groups
| Autor: | Peter R. Butchers, Claire E. Smith, Iain M. McLay, Rosemary Sasse, Keith Biggadike, Peter J. Mutch, Panayiotis A. Procopiou, Stephen A. Richards, Richard Conroy, Diane M. Coe, Edney Dean David, Stephen Barry Guntrip, Alison J. Ford, Rita Field, Brian Edgar Looker, Nicola Bevan, Michael John Monteith, Victoria J. Barrett, Valerie S. Morrison |
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| Rok vydání: | 2009 |
| Předmět: |
Models
Molecular Agonist Stereochemistry medicine.drug_class Guinea Pigs Administration Oral Biological Availability Bronchi CHO Cells In Vitro Techniques Chemical synthesis Guinea pig Structure-Activity Relationship Cricetulus Dogs In vivo Oral administration Cricetinae Microsomes Drug Discovery Cyclic AMP medicine Animals Humans Structure–activity relationship Albuterol Adrenergic beta-2 Receptor Agonists Salmeterol Xinafoate chemistry.chemical_classification 2-Hydroxyphenethylamine Sulfonamides Chemistry Muscle Smooth Stereoisomerism In vitro Rats Sulfonamide Trachea Molecular Medicine Muscle Contraction |
| Zdroj: | Journal of Medicinal Chemistry. 52:2280-2288 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm801016j |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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