Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement
DC Field | Value | Language |
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dc.contributor.author | Jeong, Yong Uk | - |
dc.contributor.author | Jin, Hyo-Eon | - |
dc.contributor.author | Lim, Hye Young | - |
dc.contributor.author | Choi, Goyeong | - |
dc.contributor.author | Joo, Hansol | - |
dc.contributor.author | Kang, Bohun | - |
dc.contributor.author | Lee, Ga-Hyun | - |
dc.contributor.author | Liu, Kwang-Hyeon | - |
dc.contributor.author | Maeng, Han-Joo | - |
dc.contributor.author | Chung, Sooyoung | - |
dc.contributor.author | Son, Gi Hoon | - |
dc.contributor.author | Jung, Jong-Wha | - |
dc.date.accessioned | 2021-07-06T01:40:59Z | - |
dc.date.available | 2021-07-06T01:40:59Z | - |
dc.date.created | 2021-06-17 | - |
dc.date.issued | 2021-06 | - |
dc.identifier.issn | 1424-8247 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/81606 | - |
dc.description.abstract | Circadian dysfunction is closely associated with an increased risk of various diseases. Considering that molecular clock machinery serves as an intrinsic time-keeping system underlying the circadian rhythm of biological processes, the modulation of the molecular clock machinery is an at-tractive therapeutic target with novel mechanisms of action. Based on the previous structure–activity relationship study of small molecule cryptochrome (CRY) inhibitors possessing an ethoxypropanoic acid moiety, non-ethoxypropanoic acid-type inhibitors have been developed by bioisosteric replace-ment. They were evaluated as potent and effective enhancers of E-box-mediated transcription, and, in particular, ester 5d and its hydrolysis product 2d exhibited desirable metabolic and pharmacokinetic profiles as promising drug candidates. Compound 2d directly bound to both CRY1 and 2 in surface plasmon resonance analyses, suggesting that the molecular target is CRY. Effects of compound 5d and 2d on suppressive action of CRY1 on CLOCK:BMAL1-activated E-box-LUC reporter activity revealed that both compounds inhibited the negative feedback actions of CRY on CLOCK:BMAL1. Most importantly, compounds 5d and 2d exhibited significant effects on molecular circadian rhythmicity to be considered circadian clock-enhancers, distinct from the previously developed CRY inhibitors possessing an ethoxypropanoic acid moiety. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | MDPI | - |
dc.relation.isPartOf | Pharmaceuticals | - |
dc.title | Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement | - |
dc.type | Article | - |
dc.type.rims | ART | - |
dc.description.journalClass | 1 | - |
dc.identifier.wosid | 000666776000001 | - |
dc.identifier.doi | 10.3390/ph14060496 | - |
dc.identifier.bibliographicCitation | Pharmaceuticals, v.14, no.6 | - |
dc.description.isOpenAccess | N | - |
dc.identifier.scopusid | 2-s2.0-85107494479 | - |
dc.citation.title | Pharmaceuticals | - |
dc.citation.volume | 14 | - |
dc.citation.number | 6 | - |
dc.contributor.affiliatedAuthor | Maeng, Han-Joo | - |
dc.type.docType | Article | - |
dc.subject.keywordAuthor | Bioisosteric replacement | - |
dc.subject.keywordAuthor | Circadian clock | - |
dc.subject.keywordAuthor | Circadian rhythm | - |
dc.subject.keywordAuthor | Cryptochrome inhibitor | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
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