Seymour A A, Asaad M M, Abboa-Offei B E, Smith P L, Rogers W L, Dorso C R
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
J Cardiovasc Pharmacol. 1996 Nov;28(5):672-8. doi: 10.1097/00005344-199611000-00010.
The natriuretic and depressor responses to novel dual inhibitors of neutral endopeptidase (NEP) EC 3.4.24.11 and angiotensin-converting enzyme (ACE) were used to assess their activity in conscious cynomolgus monkeys. A survey of mercaptopropanoyl inhibitors revealed that compounds containing alanylproline or certain surrogates reduced blood pressure and increased sodium excretion, indicating a desirable profile of in vivo activity. Additional compound evaluation required specific in vivo assays for NEP and ACE inhibition. Accordingly, the potency of novel inhibitors against NEP and ACE were determined in conscious monkeys by the potentiation of the natriuretic activity of exogenous human atrial natriuretic peptide and inhibition of the pressor response to angiotensin I, respectively. This strategy led to the discovery that optimal in vivo activity was achieved when the mercaptopropanoyl group was replaced with mercaptoacetyl and the C-terminal alanylproline was replaced with conformationally constrained dipeptidomimetics. This work culminated in the identification of BMS-182657 as a prototypic dual NEP/ACE inhibitor with a highly desirable profile of in vivo pharmacology.
利用对新型中性内肽酶（NEP，EC 3.4.24.11）和血管紧张素转换酶（ACE）双重抑制剂的利钠和降压反应，在清醒的食蟹猴中评估它们的活性。对巯基丙酰基抑制剂的一项研究表明，含有丙氨酰脯氨酸或某些替代物的化合物可降低血压并增加钠排泄，表明其具有理想的体内活性特征。进一步的化合物评估需要针对NEP和ACE抑制的特定体内试验。因此，分别通过增强外源性人心房利钠肽的利钠活性和抑制对血管紧张素I的升压反应，在清醒的猴子中测定新型抑制剂对NEP和ACE的效力。该策略导致发现，当巯基丙酰基被巯基乙酰基取代且C末端丙氨酰脯氨酸被构象受限的二肽模拟物取代时，可实现最佳的体内活性。这项工作最终确定BMS-182657为一种具有高度理想的体内药理学特征的原型双重NEP/ACE抑制剂。
