Synthesis and evaluation of potent and selective beta(3) adrenergic receptor agonists containing acylsulfonamide, sulfonylsulfonamide, and sulfonylurea carboxylic acid isosteres
| Autor: | David N. Deaton, Mark A. Paulik, Frank Lee, Kim K. Adkison, Elizabeth E. Sugg, Robert Hart, Clifton E. Hyman, Bryan W. Sherman, Timothy A. True, B.E. Reitter, David Barrett, Conrad Cowan, Mary E. Lancaster, Robert G. Hughes, Kelly Horne Donaldson, David E. Uehling |
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| Rok vydání: | 2002 |
| Předmět: |
Agonist
Male Magnetic Resonance Spectroscopy medicine.drug_class Stereochemistry Carboxylic acid Biological Availability Carboxamide CHO Cells Chemical synthesis Mass Spectrometry Body Temperature chemistry.chemical_compound Mice Radioligand Assay Structure-Activity Relationship Dogs Cricetinae Drug Discovery medicine Functional selectivity Cyclic AMP Animals Humans Carboxylate Imide Chromatography High Pressure Liquid chemistry.chemical_classification Sulfonamides Aniline Compounds Stereoisomerism Adrenergic beta-Agonists Sulfonamide Sulfonylurea Compounds chemistry Thermography Receptors Adrenergic beta-3 Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry. 45(3) |
| ISSN: | 0022-2623 |
| Popis: | Starting from phenethanolamine aniline leads 3a and 3b, we have identified a series of functionally potent and selective beta(3) adrenergic receptor (AR) agonists containing acylsulfonamide, sulfonylsulfonamide, or sulfonylurea groups within the aniline phenethanolamine series. In beta(3), beta(2), and beta(1) AR cAMP functional assays, 3a and other right-hand side (RHS) carboxylate analogues were found to be full agonists that were modestly selective against beta(1) or beta(2) ARs, while analogues lacking RHS acid functionality were active at beta(3) AR but not selective. Replacement of the carboxylate with acylthiazole and acylmethylsulfone gave potent, but only modestly selective, compounds. Increasing the size of the RHS sulfonamide substituent with phenyl or p-toluene afforded compounds with good potency and functional selectivity (beta(3) AR pEC(50) greater than 8; beta(1) and beta(2) AR selectivity greater than 40- and 500-fold, respectively). Our SAR studies suggest that the potency and selectivity profile of the best analogues reported here is a result of both the steric bulk and acidity of the RHS sulfonamide NH group. Although all of the analogues had a pharmacokinetic half-life of less than 2 h, acylsulfonamides 43 and 44 did show moderately low clearance in dogs. These two compounds were further evaluated by thermographic imaging in mice and were found to produce a robust thermogenic response via oral administration. |
| Databáze: | OpenAIRE |
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