2. Academic Validation
  3. Discovery of Brain-Penetrant Glucosylceramide Synthase Inhibitors with a Novel Pharmacophore

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

  • J Med Chem. 2022 Mar 10;65(5):4270-4290. doi: 10.1021/acs.jmedchem.1c02078.
Yuta Tanaka 1,  Masaki Seto 1,  Keiko Kakegawa 1,  Kazuaki Takami 1,  Fumiaki Kikuchi 1,  Takeshi Yamamoto 1,  Minoru Nakamura 1,  Masaki Daini 1,  Masataka Murakami 1,  Tomohiro Ohashi 1,  Takahito Kasahara 1,  Junsi Wang 1,  Zenichi Ikeda 1,  Yasufumi Wada 1,  Florian Puenner 1,  Takahiro Fujii 1,  Masakazu Inazuka 1,  Sho Sato 1,  Tomohiko Suzaki 1,  Jeong-Ho Oak 1,  Yuichi Takai 1,  Hiroshi Kohara 1,  Kouya Kimoto 1,  Hideyuki Oki 2,  Satoshi Mikami 1,  Minoru Sasaki 1,  Yuta Tanaka 1
Affiliations

Affiliations

  • 1 Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • 2 Axcelead Drug Discovery Partners, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
PMID: 35188773 DOI: 10.1021/acs.jmedchem.1c02078
Abstract

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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