| RRC ID |
62867
|
| Author |
Sakai H, Inoue H, Murata K, Toba T, Shimmyo Y, Narii N, Ueno SY, Igawa Y, Takemoto N.
|
| Title |
Fibroblast growth factor receptor modulators employing diamines with reduced phospholipidosis-inducing potential.
|
| Journal |
Bioorg Med Chem
|
| 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.
|
| Volume |
28(14)
|
| Pages |
115562
|
| Published |
2020-7-15
|
| DOI |
10.1016/j.bmc.2020.115562
|
| PII |
S0968-0896(20)30392-8
|
| PMID |
32616184
|
| MeSH |
Animals
Caco-2 Cells
Diamines / chemical synthesis
Diamines / chemistry
Diamines / pharmacology*
Dose-Response Relationship, Drug
Humans
Male
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Molecular Structure
Neurons / drug effects
Neurons / metabolism
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
Phospholipids / antagonists & inhibitors*
Phospholipids / metabolism
Rats
Rats, Wistar
Receptors, Fibroblast Growth Factor / metabolism*
Structure-Activity Relationship
|
| IF |
3.073
|
| Resource |
| Human and Animal Cells |
CACO-2(RCB0988) |
