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首页> 外文期刊>Life sciences >CGS 34043: a non-peptidic, potent and long-acting dual inhibitor of endothelin converting enzyme-1 and neutral endopeptidase 24.11.
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CGS 34043: a non-peptidic, potent and long-acting dual inhibitor of endothelin converting enzyme-1 and neutral endopeptidase 24.11.

机译：CGS 34043：内皮素转化酶1和中性内肽酶24.11的非肽，强效和长效双重抑制剂。

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摘要

Endothelin-1 (ET- 1) is a potent vasoconstrictor. Its biosynthesis is catalyzed by endothelin converting enzyme (ECE). In contrast, atrial natriuretic peptide (ANP) is a potent vasorelaxant and diuretic, and it is mainly degraded by neutral endopeptidase 24.11 (NEP). Therefore, compounds that can suppress the production of ET-1 by inhibiting ECE while simultaneously potentiating the levels of ANP by inhibiting NEP may be novel agents for the treatment of cardiovascular and renal dysfunction. CGS 34043 is one such compound, which inhibited the activities of ECE-1a and NEP with IC50 values of 5.8 and 110 nM, respectively. In vivo, it inhibited the pressor response induced by big ET-1, the precursor of ET-1, dose-dependently in rats, and the inhibition was sustained for at least 2 hr. In addition, CGS 34043 increased plasma ANP by 150% up to 4 hr after an intravenous dose of 10 mg/kg in conscious rats infused with ANP. However, this compound had no effect on the angiotensin I-induced pressor response. These results demonstrate that CGS 34043 is a potent and long-lasting dual inhibitor of ECE-1 and NEP. Consequently, it may be beneficial for the treatment of diseases in which an overproduction of ET-1 and/or enhanced degradation of ANP plays a pathogenic role. The activity of CGS 34753, an orally active prodrug of CGS 34043, is also described.
机译：内皮素-1（ET-1）是有效的血管收缩药。它的生物合成被内皮素转化酶（ECE）催化。相反，心钠素（ANP）是有效的血管舒张剂和利尿剂，并且主要被中性内肽酶24.11（NEP）降解。因此，可以通过抑制ECE抑制ET-1产生，同时通过抑制NEP增强ANP水平的化合物可能是治疗心血管和肾功能不全的新型药物。 CGS 34043是一种这样的化合物，其抑制ECE-1a和NEP的活性，IC50值分别为5.8和110 nM。在体内，它在大鼠中剂量依赖性地抑制了由大ET-1（ET-1的前体）诱导的升压反应，这种抑制作用持续至少2小时。此外，在静脉注射10 mg / kg的清醒大鼠ANP后，CGS 34043在静脉注射10 mg / kg后最多4小时，血浆ANP升高150％。然而，该化合物对血管紧张素I诱导的升压反应没有作用。这些结果证明，CGS 34043是一种有效且持久的ECE-1和NEP双重抑制剂。因此，对于其中ET-1的过量生产和/或ANP的降解增强起致病作用的疾病的治疗可能是有益的。还描述了CGS 34753（CGS 34043的口服活性前药）的活性。

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