Development of selective compounds that exclusively inhibit aldosterone synthesis for use in therapy of cardio-metabolic disorders, caused by hyperaldosteronism. Currently there is no drug on the market targeting selectively on aldosterone synthase.
According to the latest WHO data, more than 7.5 million deaths worldwide are caused by high blood pressure (hypertension), representing approximately 12.8% of total deaths. The sum of years lost due to the premature death and disability (indicator DALYs) due to hypertension is 58 million. Special attention is given to resistant forms of hypertension (RFH), when the combination of three or more antihypertensive drugs of different classes cannot eliminate the symptoms of hypertension. Patients with RFH constitute 5-30% of patients with hypertension and have more severe symptoms.
To a large extent the progression of RFH is related to the excessive aldosterone synthesis (basic human mineralocorticoid hormone). Aldosterone excess is implicated in the development and progression of several different cardiovascular/renal disease processes, including hypertension, congestive heart failure, chronic kidney disease, coronary artery disease and stroke. High aldosterone concentrations have also been associated with insulin resistance and pancreatic ?-cell dysfunction. Most prominent approach to inhibiting aldosterone-induced cardiovascular injury is to suppress its synthesis (i.e., the inhibition of aldosterone synthase). This strategy prevents the non-genomic actions of aldosterone that are not antagonized by MR blockade. Therefore aldosterone synthase (CYP11B2 or AS) has received growing attention as an attractive therapeutic target for antihypertensive drug discovery.
However, the development of selective and potent CYP11B2 inhibitors is particularly challenging due to high homology to the CYP11B1 isoform (93% amino acid sequence identity with CYP11B2) and other steroidogenic enzymes, especially in the absence of structural information. The progress in AS research was hampered for a long time by the inability to obtain a purified protein due to its low stability and membrane nature and as a result no adequate screening systems available.
CRISTA plarform enabled to identify four different scaffolds with strong inhibitory effect on aldosterone synthase — these compounds will be used for molecular docking using the crystal structure of the complex with fadrazole and for subsequent optimization.
Our compound will have a high inhibitory activity on a specific target (aldosterone synthase), have a minimal inhibitory effect on other enzymes of the steroid hormones biosynthesis and xenobiotic metabolism, and also have low toxicity.