Synthesis and pharmacology of selective non-steroidal inhibitors of 24-dehydrocholesterol reductase

• Applicants: Professor Dr. Franz Bracher; Dr. Christoph Müller
• Subject Area: Pharmacy
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508062421

In several recently published studies, the steroid desmosterol was identified as a potential drug for the treatment of neurodegenerative diseases, atherosclerosis and non-alcoholic steatohepatis (NASH). However, direct application of desmosterol is not possible due to a rapid metabolism to cholesterol. Desmosterol is converted to cholesterol by the enzyme 24-dehydrocholesterol reductase (DHCR24). Inhibition of DHCR24 leads to an accumulation of the endogenously active compound desmosterol. For the exploration of the therapeutic potential of DHCR24 inhibitors, however, only one potent steroidal inhibitor (SH42, IC50 4 nM) is currently available, as well as a few less selective and less potent non-steroidal inhibitors, such as amiodarone (IC50 1 µM) and orphenandrine (IC50 16 µM). Despite the extremely promising activity of SH42, further optimization towards a candidate for clinical trials is very difficult. The reason for this is the very limited possibility of systematically varying this compound. Therefore, in principle, non-steroidal lead structures that can be produced fully synthetically are more suitable for a program for the development of drug candidates. The aim of this project is the development of potent non-steroidal DHCR24 inhibitors based on the antiarrhythmic drug amiodarone. The drug candidates should be more active at DHCR24 compared to the lead structure with no proarrhythmic activity. Furthermore, the substances should not have any side effects typical of amioadrone, such as hypothyroidism, or unacceptably long half-lives. Due to its clear structure and the option of synthesizing almost any analog according to a viable "building block system", amiodarone opens up a wide range of optimization possibilities. Briefly, our considerations for improving the pharmacological properties are as follows: Amiodarone-induced hypothyroidism should be minimized by eliminating the two iodine substituents or replacing them with other residues. A shortening of the half-life of amiodarone should be achieved by introducing polar residues or by eliminating or reducing lipophilic residues. The substitution of the benzofuran ring system by other aromatics should lead to a reduction in the proarrhythmic activity, since this bicycle, along with the diaryl ketone partial structure, is held responsible for this effect. The synthesized substances will be tested for DHCR24 activity in our in vitro assays, selective and potent candidates will be further tested for their proarrhythmic activity. In order to explore a possible field of application for DHCR24 inhibitors, the most promising compound will finally be tested in a NASH mouse model.

• DFG Programme: Research Grants
• International Connection: Netherlands
• Cooperation Partners: Professor Dr.-Ing. Martin Giera; Professor Dr. Patrick C.N. Rensen