The project is on LEAD OPTIMIZATION stage.
The mineralocorticoid hormone aldosterone is an important regulator of blood pressure and electrolyte balance. However, excess aldosterone can be deleterious as a driver of processes, that lead to maladaptive cardiovascular and renal remodeling inflammation, insulin resistance, tissue fibrosis endothelial dysfunction, glomerular hyperfiltration, and excess glomerular and tubular leakage of albumin, associated with cardiometabolic disorders such as resistant arterial hypertension, chronic heart failure, chronic kidney disease and diabetic nephropathy. Mineralocorticoid receptor antagonists (MRA) and renin-angiotensin-aldosterone system (RAAS) antagonists are current clinical therapies used to antagonize deleterious effects of aldosterone in patients. MRAs compete with aldosterone for binding at its cognate receptor thereby limiting its effect while RAAS antagonists reduce aldosterone levels indirectly by blocking the stimulatory effect of angiotensin. Both MRAs and RAAS antagonists can result in incomplete inhibition of the harmful effects of excess aldosterone, and MRAs even lead to overexpression of aldosterone. Additionally, some studies demonstrate that the current clinical practice of using MR antagonists for primary hyperaldosteronism fail to abrogate the excess risk for cardiometabolic outcomes (primary outcome) as well as death, atrial fibrillation, and diabetes (secondary outcomes) compared with similar patients with essential hypertension and, therefore, a more aggressive and multi-faceted approach to medical therapy may be needed.
Aldosterone synthase (AS, CYP11B2) inhibitors (ASI) attenuate the production of aldosterone directly, predicted to have a distinct pharmacodynamics profile and have been proposed as an alternative to MRAs and RAS blockers.
Additionally, cortisol synthase (CS, CYP11B1) is an enzyme closely related to AS and responsible for generating the important glucocorticoid cortisol, required for maintaining critical metabolic and immune responses. The importance of selectivity against CS is shown by early examples of ASIs, that were only modestly selective and as such, attenuated cortisol responses when evaluated in patients. The enzymes encoded by these CYP11B1 and CYP11B2 genes share 93% amino acid sequence identity.
The project aims to discover a selective CYP11B2 inhibitors – a first-in-class drug, that doesn’t show suppression of CYP11B1 and other human CYPs, having an excellent efficacy and selectivity profile.