Discovery of Brain-Penetrant Glucosylceramide Synthase Inhibitors with a Novel Pharmacophore.

Tanaka Y, Seto M, Kakegawa K, Takami K, Kikuchi F, Yamamoto T, Nakamura M, Daini M, Murakami M, Ohashi T, Kasahara T, Wang J, Ikeda Z, Wada Y, Puenner F, Fujii T, Inazuka M, Sato S, Suzaki T, Oak JH, Takai Y, Kohara H, Kimoto K, Oki H, Mikami S, Sasaki M, Tanaka Y.

J Med Chem · 2022-02-21

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Inhibition of glucosylceramide synthase (GCS) is a major therapeutic strategy for Gaucher's disease and has been suggested as a potential target for treating Parkinson's disease. Herein, we report the discovery of novel brain-penetrant GCS inhibitors. Assessment of the structure-activity relationship revealed a unique pharmacophore in this series. The lipophilic ortho-substituent of aromatic ring A and the appropriate directionality of aromatic ring B were key for potency. Optimization of the absorption, distribution, metabolism, elimination, toxicity (ADMETox) profile resulted in the discovery of T-036, a potent GCS inhibitor in vivo. Pharmacophore-based scaffold hopping was performed to mitigate safety concerns associated with T-036. The ring opening of T-036 resulted in another potent GCS inhibitor with a lower toxicological risk, T-690, which reduced glucosylceramide in a dose-dependent manner in the plasma and cortex of mice. Finally, we discuss the structural aspects of the compounds that impart a unique inhibition mode and lower the cardiovascular risk.

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