Bispecific small molecule for treatment of metabolic syndrome, chronic kidney disease, NAFLD, NASH
Prof. Eugen Proschak, Goethe University Frankfurt am Main; Dr Daniel Merk, Goethe University Frankfurt am Main; Prof. John Imig, Medical College of Wisconsin; Dr Abdul Hye Khan, Medical College of Wisconsin; Dr Jurema Schmidt, Goethe-University Frankfurt; Prof. Manfred Schubert-Zsilavecz, Goethe-University Frankfurt; Moritz Helmstädter, Goethe-University Frankfurt
Chronic kidney disease (CKD) manifistates especially in the context of the metabolic syndrome, which is a complex disease cluster requiring polypharmaceutical treatment, coming together with insufficient efficacy, drug-drug interactions and bad compliance. It requires polypharmcological compounds which simultaneously interfere with fibrotic and inflammatory components of CKD for increased efficacy.
Non-alcoholic fatty liver disease and NASH are characterized by accumulation of fat in liver potentially causing inflammation and fibrosis. NASH evolves as serious health burden with alarming incidence. There is no satisfying pharmacological therapy to meet the high medical need to date. Considering the disease’s multifactorial nature, modulation of more than one target might provide a superior therapeutic effect.
The developed compound DM509 is a dual modulator of the farnesoid X receptor (FXR) and an inhibitor of the enzyme soluble epoxide hydrolase (sEH). Previous publication has demonstrated that dual modulation of both targets has synergistic effects in rodent disease models of the metabolic syndrome (MetS). DM509 demonstrated excellent pharmacokinetic properties in mice. Four independent mouse studies, STAM NASH, diet induced NASH, DIO NASH and UUO induced kidney fibrosis were conducted. The DM509 treatment reduced fibrosis stage in 50% of animals in DIO NASH model, given 10 mg/kg*day in drinking water. In addition, agent pre-treatment prevented renal fibrosis in UUO with 54% lower Collagen positive area and 40-60% lower mRNA expression of fibrotic markers than vehicle.
Metabolic Syndrome (MetS) is a multifactorial disease comprised of dyslipidemia, cardiovascular disease, obesity & type 2 diabetes mellitus (T2D). Drugs on the market for the treatment of T2D, obesity, hypertension, & end organ damage (including chronic kidney disease & heart failure) come with adverse side effects. MetS patients also take lipid lowering & anti-platelet agents to prevent end-organ damage & mortality. In spite of multidrug regimens, end organ damage is increasing & mortality remains a serious concern. Our compounds address this unmet medical need for safer, less toxic FXR & sEH modulators that treat MetS and also protect the kidney. DM509 simultaneously treats metabolic components of MetS including NAFLD & NASH.
Tested in animal models. Four independent mouse studies: STAM NASH, diet induced NASH, DIO NASH and UUO induced kidney fibrosis.
The compound DM509 is protected by patent family PCT/EP2018/063699 filed on May 24th, 2017. Proceedings are ongoing in 14 nations. Patent family US 62/902,771 with priority 2019-09-19 focusses on the indication kidney disease and fibrosis.
J Med Chem. 2017 ;60,7703-7724