Aldosterone is a steroid hormone that promotes increased blood pressure, inflammation and fibrosis. The final three steps of its biosynthesis are catalyzed by CYP11B2 (aldosterone synthase). A closely related enzyme, CYP11B1, catalyzes the biosynthesis of cortisol, an important regulator of glucose metabolism. Small molecule inhibitors of CYP11B2 such as LCI699 have recently been shown to lower aldosterone levels and blood pressure in the clinic, thus validating this mechanism as a treatment for hypertension. LCI699, which inhibits CYP11B2 with only modest selectivity vs. CYP11B1, also produces an undesired impairment of cortisol response, presumably as result of CYP11B1 inhibition. More selective inhibitors of CYP11B2 are thus desired as treatments for hypertension.<br/>This talk will highlight the discovery and optimization of several structurally distinct series of CYP11B2 inhibitors. These efforts culminated in the identification of key compounds that display potent CYP11B2 inhibition, high selectivity versus related CYPs, good pharmacokinetic properties in rat and rhesus, and good physical properties. In a rhesus pharmacodynamic model, key compounds display dose dependent aldosterone lowering efficacy, with signifcant reductions in plasma aldosterone, and no apparent effect on cortisol levels.

Discovery of selective CYP11B2 inhibitors as potential treatments for resistant hypertension

254th National Meeting (2017)

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