CEA, DSV, Service d'Ingenierie Moleculaire des Proteines (SIMOPRO), Bat 152, CE-Saclay, Gif/Yvette 91191 Cedex, France.
J Med Chem. 2010 Jan 14;53(1):208-20. doi: 10.1021/jm9010803.
A new series of phosphinic inhibitors able to interact with both angiotensin-converting enzyme (ACE) C-domain and endothelin-converting enzyme-1 (ECE-1), while sparing neprilysin (NEP), has been developed. The most potent and selective inhibitor in this series (compound 8(F2)) displays K(i) values of 0.65 nM, 150 nM, 14 nM and 6.7 microM toward somatic ACE C-domain, ACE N-domain, ECE-1, and NEP, respectively. Remarkably, in this series, the inhibitor's ability to discriminate between ECE-1 and NEP was observed to depend on the stereochemistry of the residue present in the inhibitor's P(1)' position. After iv administration, compound 8(F2) (10 mg/kg) lowered mean arterial blood pressure by 24 +/- 2 mmHg in spontaneously hypertensive rats, as compared with controls. Mixed ACE/ECE-1 inhibitor may lead to a new generation of vasopeptide inhibitors that should reduce the levels of angiotensin-II and endothelin-1, without interfering with bradykinin cleavage.
已经开发出了一系列能够与血管紧张素转换酶（ACE）C 结构域和内皮素转换酶-1（ECE-1）相互作用，同时不抑制 Neprilysin（NEP）的新型膦酸抑制剂。在这个系列中，最有效和选择性的抑制剂（化合物 8(F2)) 对体细胞 ACE C 结构域、ACE N 结构域、ECE-1 和 NEP 的 K(i) 值分别为 0.65 nM、150 nM、14 nM 和 6.7 microM。值得注意的是，在这个系列中，观察到抑制剂区分 ECE-1 和 NEP 的能力取决于抑制剂 P(1)’位置上存在的残基的立体化学。静脉注射给予化合物 8(F2)（10 mg/kg）后，与对照组相比，自发性高血压大鼠的平均动脉血压降低了 24 +/- 2 mmHg。混合 ACE/ECE-1 抑制剂可能会导致新一代的血管肽抑制剂，这些抑制剂应降低血管紧张素-II 和内皮素-1 的水平，而不会干扰缓激肽的裂解。
