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New Non-Peptide Endothelin-A Receptor Antagonists: Synthesis, Biological Properties, and Structure−Activity Relationships of 5-(Dimethylamino)- N -pyridyl-, - N -pyrimidinyl-, - N -pyridazinyl-, and - N -pyrazinyl-1-naphthalenesulfonamides

1997; American Chemical Society; Volume: 40; Issue: 6 Linguagem: Inglês

10.1021/jm9604585

1520-4804

Robert H. Bradbury, Colin Bath, Roger J. Butlin, Michael Robert Dennis, Christine Heys, Sarah J. Hunt, Roger F.L. James, Andrew Mortlock, Neil Sumner, Eric Tang, B. Telford, Elaine Whiting, Campbell Wilson,

Phosphodiesterase function and regulation

Use of automated synthesis led to the discovery of several 6-membered nitrogen heterocycles as replacements for the N-isoxazolyl substituent present in the 1-naphthalenesulfonamides endothelin-A (ETA) antagonist 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesu lfo namides (BMS 182874). In each of these heterocycles, a small substituent such as halogen para to the position of attachment to the sulfonamide nitrogen atom was found to be advantageous for ETA receptor affinity. Of these heterocycles, 2-pyrazines offered the greatest scope for improving receptor affinity. Optimization of the substituents at the 3- and 5-positions in the pyrazine ring led to potent, ETA-selective compounds such as 5-(dimethylamino)-N-(5-chloro-3-methoxy-2-pyrazinyl)-1- naphthalenesulfonamides (7m, ETA pIC50 8.1). When dosed orally at 10 mg/kg to conscious, normotensive rats infused with big ET-1, compounds such as 7m showed significant inhibition of the pressor response with a duration of effect lasting for the 5-h course of the experiment.