Design, Synthesis, and Biological Evaluations of Pyridyl 4,5,6,7-Tetrahydro-4,7-Methanobenzo[d]isoxazoles as Potent and Selective Inhibitors of 11β-Hydroxylase
Design, Synthesis, and Biological Evaluations of Pyridyl 4,5,6,7-Tetrahydro-4,7-Methanobenzo[d]isoxazoles as Potent and Selective Inhibitors of 11β-Hydroxylase
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吡啶基 4,5,6,7-四氢-4,7-MethanoBenz[d]异恶唑作为 11β-羟化酶的有效和选择性抑制剂的设计、合成和生物学评价
DOI：
10.1021/acs.jmedchem.2c01037
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发表时间：
2022-08-17
影响因子：
7.3
通讯作者：
Hu，Qingzhong
中科院分区：
文献类型：
--
作者：
Yin，Lina;Pan，Youtian;Hu，Qingzhong
抑制CYP 11B 1是治疗皮质醇过多引起的严重疾病的一种有前途的方法。对映体鉴别提供了线索，以实现选择性，CYP 11B 1和同源CYP 11B 2选择性结合S-和R-法倔唑，分别在不同的结合模式。吡啶基4，5，6，7-四氢-4，7-亚甲基苯并[d]异恶唑与S-法倔唑在CYP 11B 1中具有相似的结合模式，被设计为有效和选择性的CYP 11B 1抑制剂。化合物7aa表现出与药物奥西洛司他相似的高效CYP 11 B1抑制（IC 50分别为9和6 nM），但与奥西洛司他相比，其选择性是CYP 11 B2的1500倍（选择性因子分别为125对0.08）。口服化合物7aa可显著降低大鼠血浆皮质醇浓度，但不干扰醛固酮的产生。它对一组类固醇生成酶和肝脏CYP酶没有显示出抑制作用。化合物7aa表现出良好的药代动力学特征，被认为是进一步开发的候选药物。
Inhibition of CYP11B1 is a promising therapy for severe diseases caused by excessive cortisol. Enantiomer discrimination provides clues to achieve selectivity that CYP11B1 and homologous CYP11B2 were selectively bound byS- andR-fadrozole, respectively, in distinct binding modes. Pyridyl 4,5,6,7-tetrahydro-4,7-methanobenzo[d]isoxazoles showing a similar binding mode toS-fadrozole in CYP11B1 were designed as potent and selective CYP11B1 inhibitors. Compound7aaexhibited a highly potent CYP11B1 inhibition similar to that of the drug osilodrostat (IC50’s of 9 and 6 nM, respectively) but was 1500-fold more selective over CYP11B2 compared to osilodrostat (selectivity factors of 125versus0.08, respectively). Strong reductions of plasma cortisol concentrations by compound7aawere demonstrated in rats without interference in aldosterone production after oral application. It showed no inhibition against a panel of steroidogenic and hepatic CYP enzymes. Exhibiting a good pharmacokinetic profile, compound7aawas considered as a drug candidate for further development.