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
  • 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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