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Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT2C Agonists.

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.

SUBMITTER: Kim J

PROVIDER: S-EPMC6767204 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT2C Agonists.

Kim Juhyeon J Kim Yoon Jung YJ Londhe Ashwini M AM Pae Ae Nim AN Choo Hyunah H Kim Hak Joong HJ Min Sun-Joon SJ

Molecules (Basel, Switzerland) 20190905 18

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</s ...[more]

PMID: 31491978

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