Design and synthesis of a potent and selective endothelin-converting enzyme inhibitor, CGS 35066

CGS 26303 has previously been shown to inhibit human endothelin converting enzyme-1 (ECE-1) with an IC50 of 410 nM and to be efficacious in several an imal disease models. However, it is a more potent inhibitor of neutral endo peptidase 24.11 (NEP) with an IC50 of 1 nM. The aim of this study was to op timize CGS 26303 for greater potency and selectivity towards ECE-1 inhibiti on. The in vivo activity of the compounds was assessed by inhibition of the big endothelin-1 (ET-1)-induced pressor response in anesthetized rats at 9 0 min after treatment with a dose of 10 mg/kg, i.v. Under these conditions, CGS 26303 inhibited the presser response to big ET-1 by 50%. Replacement o f the biphenyl and tetrazol groups in CGS 26303 with a dibenzofuran and car boxylic acid, respectively, yielded CGS 35066, a potent ECE-1 inhibitor hav ing an IC50 of 22 nM. In contrast, these substitutions markedly weakened th e NEP inhibitory activity of the compound to an IC50 of 2.3 muM. CGS 35066 also exhibited a potent and sustained ECE-1 inhibitory activity in vivo, bl ocking the presser response to big ET-1 by 84%. Its orally active prodrug, CGS 35339, was obtained by introducing two phenyl groups at the phosphonic acid substituent in CGS 35066. Therefore, CGS 35066 and CGS 35339 represent novel compounds for assessing the pathogenic role of ET-1 overproduction i n various disease states.