Development and in vitro Profiling of Dual FXR/LTA4H Modulators.

Simone Schierle, Steffen Brunst, Moritz Helmstädter, Roland Ebert, Jan S Kramer, Dieter Steinhilber, Ewgenij Proschak, Daniel Merk

ChemMedChem 2021 Aug 05

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Designed polypharmacology presents as an attractive strategy to increase therapeutic efficacy in multi-factorial diseases by a directed modulation of multiple involved targets with a single molecule. Such an approach appears particularly suitable in non-alcoholic steatohepatitis (NASH) which involves hepatic steatosis, inflammation and fibrosis as pathological hallmarks. Among various potential pharmacodynamic mechanisms, activation of the farnesoid X receptor (FXRa) and inhibition of leukotriene A4 hydrolase (LTA4Hi) hold promise to counteract NASH according to preclinical and clinical observations. We have developed dual FXR/LTA4H modulators as pharmacological tools, enabling evaluation of this polypharmacology concept to treat NASH and related pathologies. The optimized FXRa/LTA4Hi exhibits well-balanced dual activity on the intended targets with sub-micromolar potency and is highly selective over related nuclear receptors and enzymes rendering it suitable as tool to probe synergies of dual FXR/LTA4H targeting. © 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.

Citation

Simone Schierle, Steffen Brunst, Moritz Helmstädter, Roland Ebert, Jan S Kramer, Dieter Steinhilber, Ewgenij Proschak, Daniel Merk. Development and in vitro Profiling of Dual FXR/LTA4H Modulators. ChemMedChem. 2021 Aug 05;16(15):2366-2374