Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT<sub>2C</sub> Agonists
Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT<sub>2C</sub> agonists. To improve selectivity for 5-HT<sub>2C</sub> over other subtypes, we synthesized two series of disubstituted pyrimidines with fluor...
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MDPI AG
2019-09-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/18/3234 |
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| author | Juhyeon Kim Yoon Jung Kim Ashwini M. Londhe Ae Nim Pae Hyunah Choo Hak Joong Kim Sun-Joon Min |
| author_facet | Juhyeon Kim Yoon Jung Kim Ashwini M. Londhe Ae Nim Pae Hyunah Choo Hak Joong Kim Sun-Joon Min |
| author_sort | Juhyeon Kim |
| collection | DOAJ |
| description | Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT<sub>2C</sub> agonists. To improve selectivity for 5-HT<sub>2C</sub> 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 <b>10a</b> and <b>10f</b> as potent 5-HT<sub>2C</sub> agonists. Further studies on selectivity to 5-HT subtypes and drug-like properties indicated that 2,4-disubstituted pyrimidine <b>10a</b> showed a highly agonistic effect on the 5-HT<sub>2C</sub> receptor, with excellent selectivity, as well as exceptional drug-like properties, including high plasma and microsomal stability, along with low CYP inhibition. Thus, pyrimidine <b>10a</b> could be considered a viable lead compound as a 5-HT<sub>2C</sub> selective agonist. |
| first_indexed | 2024-04-11T23:29:13Z |
| format | Article |
| id | doaj.art-8e918d4918b149c5b267ed92a279987b |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-11T23:29:13Z |
| publishDate | 2019-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-8e918d4918b149c5b267ed92a279987b2022-12-22T03:57:13ZengMDPI AGMolecules1420-30492019-09-012418323410.3390/molecules24183234molecules24183234Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT<sub>2C</sub> AgonistsJuhyeon Kim0Yoon Jung Kim1Ashwini M. Londhe2Ae Nim Pae3Hyunah Choo4Hak Joong Kim5Sun-Joon Min6Center for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Seoul 02792, KoreaDepartment of Applied Chemistry, Hanyang University, Ansan, Gyeonggi-do 15588, KoreaDivision of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, KoreaDivision of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, KoreaCenter for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Seoul 02792, KoreaDepartment of Chemistry, Korea University, Seoul 02841, KoreaDepartment of Applied Chemistry, Hanyang University, Ansan, Gyeonggi-do 15588, KoreaHere, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT<sub>2C</sub> agonists. To improve selectivity for 5-HT<sub>2C</sub> 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 <b>10a</b> and <b>10f</b> as potent 5-HT<sub>2C</sub> agonists. Further studies on selectivity to 5-HT subtypes and drug-like properties indicated that 2,4-disubstituted pyrimidine <b>10a</b> showed a highly agonistic effect on the 5-HT<sub>2C</sub> receptor, with excellent selectivity, as well as exceptional drug-like properties, including high plasma and microsomal stability, along with low CYP inhibition. Thus, pyrimidine <b>10a</b> could be considered a viable lead compound as a 5-HT<sub>2C</sub> selective agonist.https://www.mdpi.com/1420-3049/24/18/3234disubstituted pyrimidine5-HT<sub>2C</sub> receptorcell-based assaybinding affinityselectivity |
| spellingShingle | Juhyeon Kim Yoon Jung Kim Ashwini M. Londhe Ae Nim Pae Hyunah Choo Hak Joong Kim Sun-Joon Min Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT<sub>2C</sub> Agonists Molecules disubstituted pyrimidine 5-HT<sub>2C</sub> receptor cell-based assay binding affinity selectivity |
| title | Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT<sub>2C</sub> Agonists |
| title_full | Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT<sub>2C</sub> Agonists |
| title_fullStr | Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT<sub>2C</sub> Agonists |
| title_full_unstemmed | Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT<sub>2C</sub> Agonists |
| title_short | Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT<sub>2C</sub> Agonists |
| title_sort | synthesis and biological evaluation of disubstituted pyrimidines as selective 5 ht sub 2c sub agonists |
| topic | disubstituted pyrimidine 5-HT<sub>2C</sub> receptor cell-based assay binding affinity selectivity |
| url | https://www.mdpi.com/1420-3049/24/18/3234 |
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