Aldosterone is an important regulator of blood pressure and electrolyte balance, but its excess in plazma concentration can be a driver of processes, that lead to maladaptive cardiovascular and renal remodeling, inflammation, insulin resistance, tissue fibrosis endothelial dysfunction, glomerular hyperfiltration  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. 

Tuberculosis is one of the top 10 causes of death worldwide and the leading cause from a single infectious agent (above HIV/AIDS). Millions of people continue to fall sick with TB each year. In 2017, TB caused an estimated 1.3 million deaths (range, 1.2–1.4 million) among HIV-negative people and there were an additional 300 000 deaths from TB (range, 266 000–335 000) among HIV-positive people. Globally, the best estimate is that 10.0 million people (range, 9.0–11.1 million) developed TB disease in 2017: 5.8 million men, 3.2 million women and 1.0 million children.

Mycobacteria tuberculosis can develop resistance to the antimicrobial drugs used to cure the disease. Multidrug-resistant TB (MDR-TB) is TB that does not respond to at least isoniazid and rifampicin, the 2 most powerful anti-TB drugs. In 2016, an estimated 490 000 people worldwide developed MDR-TB, and an additional 110 000 people with rifampicin-resistant TB were also newly eligible for MDR-TB treatment. The countries with the largest numbers of MDR/RR-TB cases (47% of the global total) were China, India and the Russian Federation. It is estimated that about 6.2% of these cases were XDR-TB. Moreover, strains resistant to all existed drugs (TDR-TB) have been reported in recent years. Extensively drug-resistant TB, XDR-TB, is a form of multidrug-resistant TB with additional resistance to more anti-TB drugs that therefore responds to even fewer available medicines. It has been reported in 117 countries worldwide. [1] 

That facts drives the market demand in novel anti-TB drugs aiming on alternative targets to improve current treatment protocols.

Search and validation of new drug targets is the basis for discovery of innovative anti-TB agents. In this context Mycobacterium tuberculosis (MT) genome revealed unexpectedly large number of cytochromes P450 (CYPs) – 20 isoforms – that are highly conserved among pathogenic mycobacteria and some of them have been associated with virulence. Blocking MT CYPs activity appears as a potential pharmacological therapy of TB [2].

Analyzis of CYPs genes of drug-resistant and drug-sensitive strains MT strains from the Tuberculosis Portals program (TBPP) database [3] revealed the absence of nonsense or frameshift mutations in most enzymes. Moreover, for some CYP proteins, a high degree of correlation between amino-acid substitutions and the development of resistance to certain type of antibiotics was observed. It was revealed, that MT CYPs could be involved in modulation of oxysterol and vitamin D synthesis [4] that might be another adaptation mechanism of mycobacteria to escape human immune system.

Inspired by accumulated scientific data and proprietary achievements MT-Medicals LLC develops first-in-class anti-tuberculosis drug that targets certain CYPs of mycobacteria.

We are targeting of Cytochromes P450 to enchance our pipeline potential in diversified indications:

• Women‘s health (endometriosis, PCOS and some forms of  breast cancer)
• Neurodegenerative diseases 
• NASH
• Chronic kidney disease