IDENTIFICATION OF A NEW CLASS OF ET(A) SELECTIVE ENDOTHELIN ANTAGONISTS BY PHARMACOPHORE DIRECTED SCREENING

Novel endothelin antagonists were identified through a ''pharmacophore directed screening'' strategy. The sulfanilamide antibacterial agent sulfisoxazole was found to be a good endothelin receptor antagonist (IC50's of 0.60 mu M and 22 mu M for the ET(A) and ET(B) receptors, respectively). The structurally similar sulfamethoxazole was found to be a weaker antagonist (IC50 for ET(A) 16 mu M and for ET(B) 230 mu M). These compounds represent a new class of low molecular weight and ET(A)-selective non-peptide endothelin antagonists. (C) 1994 Academic Press, Inc.