Discovery of 5-phenyl-3-ureidothiophene-2-carboxamides as protective agents for ALS patient iPSC-derived motor neurons

  • Bioorg Med Chem Lett. 2024 Sep 3:113:129935. doi: 10.1016/j.bmcl.2024.129935.
Haruhiko Hattori  1 ,  Kazuya Osumi  2 ,  Masamichi Tanaka  2 ,  Tadamasa Arai  2 ,  Kazumi Nishimura  2 ,  Naoyoshi Yamamoto  2 ,  Keiko Sakamoto  2 ,  Yasufumi Goto  2 ,  Yuji Sugawara  2
Affiliations
  • 1. Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: [email protected].
  • 2. Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
PMID: 39236792 DOI: 10.1016/j.bmcl.2024.129935
Abstract

We discovered novel neuroprotective compounds by phenotypic screening using SOD1-mutant amyotrophic lateral sclerosis (ALS) patient induced pluripotent stem cell (iPSC)-derived motor neurons. Mechanistic analysis showed that the protective effect of initial hit compound 1 was likely due to the inhibition of MAP4Ks, including MAP4K4, a member of the MAP4K kinase family. Structural transformation led to compound 15f, which showed improved MAP4K4 inhibitory activity and superior neuroprotective effects compared to 1 in motor neurons. The results suggest that structural optimization based on MAP4K4 inhibitory activity might improve the neuroprotective effect of this series of compounds.

Keywords
Neuroprotective; Patient iPSCs; Phenotypic screening.
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