Fibroblast growth factor receptor modulators employing diamines with reduced phospholipidosis-inducing potential

  • Bioorg Med Chem. 2020 Jul 15;28(14):115562. doi: 10.1016/j.bmc.2020.115562.
Hiroki Sakai  1 ,  Hidekazu Inoue  2 ,  Kenji Murata  2 ,  Tetsuya Toba  2 ,  Yoshiari Shimmyo  2 ,  Nobuhiro Narii  2 ,  Shin-Ya Ueno  2 ,  Yoshiyuki Igawa  2 ,  Naohiro Takemoto  2
Affiliations
  • 1. Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. Electronic address: [email protected].
  • 2. Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
PMID: 32616184 DOI: 10.1016/j.bmc.2020.115562
Abstract

SUN13837 (1), a Fibroblast Growth Factor receptor modulator, has been an attractive candidate for treating neurodegenerative diseases. However, one of its metabolites, N-benzyl-4-(methylamino)piperidine (BMP), turned out to possess phospholipidosis-inducing potential (PLIP) in vitro. To obtain SUN13837 analogs with reduced phospholipidosis risk, we replaced BMP with Other diamines possessing low PLIP. Our effort led to the discovery of compound 6 with increased efficacy. Further structural modifications to reduce hydrogen bond donors afforded 17 with improved brain exposure. Oral administration of 17 at 1 mg/kg once daily for 10 days showed enhanced recovery of coordinated movement in a rat acute stroke model, suggesting that it is a promising follow-up compound for 1 with reduced risk of phospholipidosis.

Keywords
Brain Kp; FGFR modulator; P-gp; PAMPA; Phospholipidosis.
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