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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. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Hiroki Sakai, Hidekazu Inoue, Kenji Murata, Tetsuya Toba, Yoshiari Shimmyo, Nobuhiro Narii, Shin-Ya Ueno, Yoshiyuki Igawa, Naohiro Takemoto. Fibroblast growth factor receptor modulators employing diamines with reduced phospholipidosis-inducing potential. Bioorganic & medicinal chemistry. 2020 Jul 15;28(14):115562

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PMID: 32616184

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