Abstract：
: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 animal disease models. However, it is a more potent inhibitor of neutral endopeptidase 24.11 (NEP) with an IC50 of 1 nM. The aim of this study was to optimize CGS 26303 for greater potency and selectivity towards ECE-1 inhibition. 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 90 min after treatment with a dose of 10 mg/kg, i.v. Under these conditions, CGS 26303 inhibited the pressor response to big ET-1 by 50%. Replacement of the biphenyl and tetrazol groups in CGS 26303 with a dibenzofuran and carboxylic acid, respectively, yielded CGS 35066, a potent ECE-1 inhibitor having an IC50 of 22 nM. In contrast, these substitutions markedly weakened the NEP inhibitory activity of the compound to an IC50 of 2.3 microM. CGS 35066 also exhibited a potent and sustained ECE-1 inhibitory activity in vivo, blocking the pressor 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 in various disease states.
journal_name
J Cardiovasc Pharmacoljournal_title
Journal of cardiovascular pharmacologyauthors
Jeng AY,De Lombaert S,Beil ME,Bruseo CW,Savage P,Chou M,Trapani AJdoi
10.1097/00005344-200036051-00014subject
Has Abstractpub_date
2000-11-01 00:00:00pages
S36-9issue
5 Suppl 1eissn
0160-2446issn
1533-4023journal_volume
36pub_type
杂志文章abstract：:Analysis of the circadian distributions of silent ischemic episodes and myocardial infarction has revealed a circadian variability with peak event incidences in the morning hours after awakening. This morning peak of ischemic events is paralleled by circadian variations of blood pressure and heart rate that reflect an...
journal_title：Journal of cardiovascular pharmacology
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journal_title：Journal of cardiovascular pharmacology
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journal_title：Journal of cardiovascular pharmacology
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journal_title：Journal of cardiovascular pharmacology
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pub_type： 杂志文章
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journal_title：Journal of cardiovascular pharmacology
pub_type： 杂志文章,评审
doi：
更新日期：1989-01-01 00:00:00
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journal_title：Journal of cardiovascular pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
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更新日期：1995-01-01 00:00:00
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journal_title：Journal of cardiovascular pharmacology
pub_type： 杂志文章
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journal_title：Journal of cardiovascular pharmacology
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journal_title：Journal of cardiovascular pharmacology
pub_type： 杂志文章
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pub_type： 杂志文章,评审
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pub_type： 临床试验,杂志文章,多中心研究,随机对照试验
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journal_title：Journal of cardiovascular pharmacology
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更新日期：1995-01-01 00:00:00
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更新日期：1995-01-01 00:00:00
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更新日期：2020-08-01 00:00:00
