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Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT(2C) Agonists
Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT(2C) agonists. To improve selectivity for 5-HT(2C) over other subtypes, we synthesized two series of disubstituted pyrimidines with fluorophenylalkoxy groups at either the 5-posit...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767204/ https://www.ncbi.nlm.nih.gov/pubmed/31491978 http://dx.doi.org/10.3390/molecules24183234 |
Sumario: | Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT(2C) agonists. To improve selectivity for 5-HT(2C) over other subtypes, we synthesized two series of disubstituted pyrimidines with fluorophenylalkoxy groups at either the 5-position or 4-position and varying cyclic amines at the 2-position. The in vitro cell-based assay and binding assay identified compounds 10a and 10f as potent 5-HT(2C) agonists. Further studies on selectivity to 5-HT subtypes and drug-like properties indicated that 2,4-disubstituted pyrimidine 10a showed a highly agonistic effect on the 5-HT(2C) receptor, with excellent selectivity, as well as exceptional drug-like properties, including high plasma and microsomal stability, along with low CYP inhibition. Thus, pyrimidine 10a could be considered a viable lead compound as a 5-HT(2C) selective agonist. |
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