1025829-32-6Relevant academic research and scientific papers
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
Bradbury, Robert H.,Bath, Colin,Butlin, Roger J.,Dennis, Michael,Heys, Christine,Hunt, Sarah J.,James, Roger,Mortlock, Andrew A.,Sumner, Neil F.,Tang, Eric K.,Telford, Berwick,Whiting, Elaine,Wilson, Campbell
, p. 996 - 1004 (1997)
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-naphthalenesulfonamide endothelin-A (ETA) antagonist 5- (dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide (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, ET(A)-selective compounds such as 5-(dimethylamino)-N- (5-chloro-3-methoxy-2-pyrazinyl)-1-naphthalenesulfonamide (7m, ET(A) 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.
