Synthesis and biological evaluation of disubstituted pyrimidines as selective 5-HT2C agonists

Juhyeon Kim; Yoon Jung Kim; Ashwini M. Londhe; Ae Nim Pae; Hyunah Choo; Hak Joong Kim; Sun Joon Min

doi:10.3390/molecules24183234

Synthesis and biological evaluation of disubstituted pyrimidines as selective 5-HT_2C agonists

Juhyeon Kim, Yoon Jung Kim, Ashwini M. Londhe, Ae Nim Pae, Hyunah Choo, Hak Joong Kim, Sun Joon Min

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

Abstract

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.

Original language	English
Article number	3234
Journal	Molecules
Volume	24
Issue number	18
DOIs	https://doi.org/10.3390/molecules24183234
Publication status	Published - 2019 Sept 5

Bibliographical note

Funding Information:
This work was financially supported by the Korea Health Industry Development Institute (KHIDI, HI16C1677, HI17C1037), the National Research Foundation of Korea (NRF-2019R1A2C1008186) and the research fund of Hanyang University (HY-2015-N). Binding affinity data were generously provided by the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (HHSN-271-2008-00025-C).

Funding Information:
Acknowledgments: This work was financially supported by the Korea Health Industry Development Institute (KHIDI, HI16C1677, HI17C1037), the National Research Foundation of Korea (NRF-2019R1A2C1008186) and the research fund of Hanyang University (HY-2015-N). Binding affinity data were generously provided by the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (HHSN-271-2008-00025-C).

Publisher Copyright:
© 2019 by the authors.

Keywords

5-HT receptor
Binding affinity
Cell-based assay
Disubstituted pyrimidine
Selectivity

ASJC Scopus subject areas

Analytical Chemistry
Chemistry (miscellaneous)
Molecular Medicine
Pharmaceutical Science
Drug Discovery
Physical and Theoretical Chemistry
Organic Chemistry

Access to Document

10.3390/molecules24183234

Cite this

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title = "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.",

keywords = "5-HT receptor, Binding affinity, Cell-based assay, Disubstituted pyrimidine, Selectivity",

author = "Juhyeon Kim and Kim, {Yoon Jung} and Londhe, {Ashwini M.} and Pae, {Ae Nim} and Hyunah Choo and Kim, {Hak Joong} and Min, {Sun Joon}",

note = "Funding Information: This work was financially supported by the Korea Health Industry Development Institute (KHIDI, HI16C1677, HI17C1037), the National Research Foundation of Korea (NRF-2019R1A2C1008186) and the research fund of Hanyang University (HY-2015-N). Binding affinity data were generously provided by the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (HHSN-271-2008-00025-C). Funding Information: Acknowledgments: This work was financially supported by the Korea Health Industry Development Institute (KHIDI, HI16C1677, HI17C1037), the National Research Foundation of Korea (NRF-2019R1A2C1008186) and the research fund of Hanyang University (HY-2015-N). Binding affinity data were generously provided by the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (HHSN-271-2008-00025-C). Publisher Copyright: {\textcopyright} 2019 by the authors.",

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AU - Pae, Ae Nim

AU - Choo, Hyunah

AU - Kim, Hak Joong

AU - Min, Sun Joon

N1 - Funding Information: This work was financially supported by the Korea Health Industry Development Institute (KHIDI, HI16C1677, HI17C1037), the National Research Foundation of Korea (NRF-2019R1A2C1008186) and the research fund of Hanyang University (HY-2015-N). Binding affinity data were generously provided by the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (HHSN-271-2008-00025-C). Funding Information: Acknowledgments: This work was financially supported by the Korea Health Industry Development Institute (KHIDI, HI16C1677, HI17C1037), the National Research Foundation of Korea (NRF-2019R1A2C1008186) and the research fund of Hanyang University (HY-2015-N). Binding affinity data were generously provided by the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (HHSN-271-2008-00025-C). Publisher Copyright: © 2019 by the authors.

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N2 - 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.

AB - 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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