Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2.3, D-66123 Saarbrücken, Germany.
Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany.
Eur J Med Chem. 2015;96:139-50. doi: 10.1016/j.ejmech.2015.04.013. Epub 2015 Apr 8.
The inhibition of 11β-hydroxylase is a promising strategy for the treatment of Cushing's syndrome, in particular for the recurrent and subclinical cases. To achieve proof of concept in rats, efforts were paid to identify novel lead compounds inhibiting both human and rat CYP11B1. Modifications on a potent promiscuous inhibitor of hCYP11B1, hCYP11B2 and hCYP19 (compound IV) that exhibited moderate rCYP11B1 inhibition led to compound 8 as a new promising lead compound. Significant improvements compared to starting point IV were achieved regarding inhibitory potency against both human and rat CYP11B1 (IC50 values of 2 and 163 nM, respectively) as well as selectivity over hCYP19 (IC50 = 1900 nM). Accordingly, compound 8 was around 7- and 28-fold more potent than metyrapone regarding the inhibition of human and rat CYP11B1 and exhibited a comparable selectivity over hCYP11B2 (SF of 3.5 vs 4.9). With further optimizations on this new lead compound 8, drug candidates with satisfying profiles are expected to be discovered.
11β-羟化酶抑制是治疗库欣综合征的一种很有前途的策略，特别是对于复发性和亚临床病例。为了在大鼠中证明这一概念，我们努力寻找既能抑制人 CYP11B1 又能抑制大鼠 CYP11B1 的新型先导化合物。对一种强效的人 CYP11B1、人 CYP11B2 和人 CYP19 的广谱抑制剂（化合物 IV）进行修饰，得到了对大鼠 CYP11B1 具有中度抑制作用的化合物 8，这是一种很有前途的新先导化合物。与起始点 IV 相比，化合物 8 在抑制人 CYP11B1 和大鼠 CYP11B1 的活性（IC50 值分别为 2 和 163 nM）以及对人 CYP19 的选择性（IC50 = 1900 nM）方面都有显著提高。因此，化合物 8 对人 CYP11B1 和大鼠 CYP11B1 的抑制作用分别比美替拉酮强 7 倍和 28 倍，对人 CYP11B2 的选择性与美替拉酮相当（SF 为 3.5 对 4.9）。对这个新的先导化合物 8 进行进一步优化，预计会发现具有满意特性的候选药物。
