Journal article
Potent and selective non-peptidic inhibitors of endothelin-converting enzyme-1 with sustained duration of action
S De Lombaert, L Blanchard, LB Stamford, J Tan, EM Wallace, Y Satoh, J Fitt, D Hoyer, D Simonsbergen, J Moliterni, N Marcopoulos, P Savage, M Chou, AJ Trapani, AY Jeng
JOURNAL OF MEDICINAL CHEMISTRY | AMER CHEMICAL SOC | Published : 2000
DOI: 10.1021/jm990507o
Abstract
Potent and selective non-peptidic inhibitors of human endothelin-converting enzyme-1 (ECE-1) have been designed as potential modulators of endothelin (ET-1) production in vivo. Because of its unique structural characteristics and long duration of action in vivo, the dual ECE-1 and neutral endopeptidase 24.11 (NEP) inhibitor, CGS 26303, was selected as an attractive lead for further optimization of potency and selectivity. Replacement of the P(1)' biphenyl substituent of CGS 26303 by a conformationally restricted 3-dibenzofuranyl group led to more potent and more selective ECE-1 inhibitors, such as the tetrazole 27. The remarkable effect of this P(1)' modification allowed for the first time p..
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