Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT2C Agonistsopen access
- Authors
- Kim, Juhyeon; Kim, Yoon Jung; Londhe, Ashwini M.; Pae, Ae Nim; Choo, Hyunah; Kim, Hak Joong; Min, Sun-Joon
- Issue Date
- Sep-2019
- Publisher
- Multidisciplinary Digital Publishing Institute (MDPI)
- Keywords
- disubstituted pyrimidine; 5-HT2C receptor; cell-based assay; binding affinity; selectivity
- Citation
- Molecules, v.24, no.18, pp.1 - 22
- Indexed
- SCIE
SCOPUS
- Journal Title
- Molecules
- Volume
- 24
- Number
- 18
- Start Page
- 1
- End Page
- 22
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/2351
- DOI
- 10.3390/molecules24183234
- ISSN
- 1420-3049
- Abstract
- Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT2C agonists. To improve selectivity for 5-HT2C 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-HT2C 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-HT2C 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-HT2C selective agonist.
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