Dihydrobenzisoxazole-4-one compounds are novel selective inhibitors of aldosterone synthase (CYP11B2) with <em>in vivo</em> activity

6,7-Dihydro-5H-2,1-benzisoxazol-4-one analogs are potent inhibitors of aldosterone synthase (CYP11B2) with selectivity over the highly homologous enzyme cortisol synthase (CYP11B1). These compounds are unique among inhibitors of CYP11B2 in their lack of a strong-heme binding group such as a pyridine or imidazole. Poor metabolic stability in hepatocyte incubations was found to proceed via a reduction of the isoxazole ring. While the enzyme responsible for the reductive metabolism remains unknown, the rate of metabolism could be attenuated by the addition of polar functionality. The in vitro CYP11B2 potency and selectivity were confirmed in vivo in a cynomolgus monkey model by the inhibition of ACTH stimulated aldosterone production without impacting plasma cortisol concentrations.

6,7 - 二氢 - 5H - 2,1 - 苯并异噁唑 - 4 - 酮类似物是醛固酮合酶（CYP11B2）的强效抑制剂，对高度同源的酶皮质醇合酶（CYP11B1）具有选择性。这些化合物在CYP11B2抑制剂中独具特色，它们没有像吡啶或咪唑这样的强血红素结合基团。在肝细胞孵育中发现其代谢稳定性差是由于异噁唑环被还原。虽然负责还原代谢的酶仍不清楚，但通过添加极性官能团可以降低代谢速率。在食蟹猴模型中，通过抑制促肾上腺皮质激素刺激的醛固酮生成且不影响血浆皮质醇浓度，在体内证实了其体外对CYP11B2的效力和选择性。