Exorbitant aldosterone is closely associated with various severe diseases, including congestive heart failure and chronic kidney disease. As aldosterone synthase is the pivotal enzyme in aldosterone biosynthesis, its inhibition constitutes a promising treatment for these diseases. Via a structure-based approach, a series of pyridyl substituted 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-ones were designed as inhibitors of aldosterone synthase. Six compounds (5j, 5l, 5m 5w, 5x and 5y) distinguished themselves with potent inhibition (IC₅₀ <100 nmol/L) and high selectivity over homogenous 11β-hydroxylase. As the most promising compound, 5x exhibited an IC₅₀ of 12 nmol/L and an excellent selectivity factor (SF) of 157, which are both superior to those of the reference fadrazole (IC₅₀ = 21 nmol/L, SF = 7). Importantly, 5x showed no inhibition against steroidogenic CYP17, CYP19 and a panel of hepatic CYP enzymes indicating an outstanding safety profile. As it manifested satisfactory pharmacokinetic properties in rats, compound 5x was considered as a drug candidate for further development.

过高的醛固酮与各种严重疾病密切相关，包括充血性心力衰竭和慢性肾病。由于醛固酮合酶是醛固酮生物合成的关键酶，因此抑制它是治疗这些疾病的一种有希望的方法。通过基于结构的方法，一系列吡啶基取代的 3,4-二氢苯并[ f ][1,4] oxazep​​in-5(2 H )-ones 被设计为醛固酮合酶的抑制剂。六种化合物（5j、5l、5m 5w、5x和5y）具有显着的抑制作用（IC ₅₀ <100 nmol/L）和对同质 11 β 的高选择性。-羟化酶。作为最有前景的化合物，5x的 IC ₅₀为 12 nmol/L，选择性因子 (SF) 为 157，均优于参考法德拉唑 (IC ₅₀  = 21 nmol/L, SF = 7) . 重要的是，5x对类固醇生成的 CYP17、CYP19 和一组肝 CYP 酶没有抑制作用，表明其具有出色的安全性。由于它在大鼠中表现出令人满意的药代动力学特性，因此化合物5x被认为是进一步开发的候选药物。