CYP11B2 Aldosterone Synthase Inhibitor
Aldosterone is a hormone produced in the adrenal glands which helps control the body’s blood pressure by causing the kidneys to retain salt and excrete potassium, thereby increasing water retention, blood volume, and blood pressure. CYP11B2 is a member of the broad cytochrome P450 family, and is responsible for the biosynthesis of aldosterone. There are a number of diseases associated with dysregulated aldosterone, including primary hyperaldosteronism (Conn’s Syndrome), refractory hypertension, congestive heart failure and kidney fibrosis. As a result, we believe inhibition of CYP11B2 could potentially be used in aldosterone-related diseases.
The renin-angiotensin-aldosterone system (RAAS) is responsible for producing aldosterone to maintain blood pressure. Two major approaches to modulating the RAAS pathway are angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs). There are eighteen FDA-approved ACE inhibitors/ARBs. While these drugs are generally quite effective in controlling hypertension, aldosterone breakthrough or escape happens in approximately 10% to 50% of patients depending on the duration of therapy studied and the definition of ‘breakthrough’. Aldosterone excess is estimated to be the primary cause in approximately 20% of patients with resistant hypertension, or nearly 2 million patients in the United States alone.
Two mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, plus a late-stage compound (finerenone), are also involved in blocking the effects of aldosterone. MRAs act by binding to the mineralocorticoid receptor to prevent aldosterone from having its biologic effect on blood pressure and renal excretion and absorption of salt and potassium. Both approved MRAs have the downside of increasing circulating levels of aldosterone, leading to increased activity of aldosterone through its non-MR mechanisms. Aldosterone acts on the vascular system by inducing oxidative stress, inflammation, fibrosis, and endothelial dysfunction through both MR-dependent and MR-independent pathways. As such, increased levels of aldosterone has direct deleterious effects on the progression of congestive heart failure and kidney fibrosis.
We are leveraging our extensive experience in developing cytochrome P450 modulators to develop compounds with improved specificity for CYP11B2 relative to CYP11B1. In non-human primate models, one of our lead test compounds markedly reduced aldosterone production following an ACTH challenge while having a minimal impact on cortisol production.