864754-11-0Relevant academic research and scientific papers
Discovery of Brain-Penetrant Glucosylceramide Synthase Inhibitors with a Novel Pharmacophore
Daini, Masaki,Fujii, Takahiro,Ikeda, Zenichi,Inazuka, Masakazu,Kakegawa, Keiko,Kasahara, Takahito,Kikuchi, Fumiaki,Kimoto, Kouya,Kohara, Hiroshi,Mikami, Satoshi,Murakami, Masataka,Nakamura, Minoru,Oak, Jeong-Ho,Ohashi, Tomohiro,Oki, Hideyuki,Puenner, Florian,Sasaki, Minoru,Sato, Sho,Seto, Masaki,Suzaki, Tomohiko,Takai, Yuichi,Takami, Kazuaki,Tanaka, Yuta,Wada, Yasufumi,Wang, Junsi,Yamamoto, Takeshi
, p. 4270 - 4290 (2022/03/14)
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.
