Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement
| Autor: | Hansol Joo, Bohun Kang, Yong Uk Jeong, Gi Hoon Son, Han Joo Maeng, Ga Hyun Lee, Hye Young Lim, Sooyoung Chung, Hyo-Eon Jin, Jong-Wha Jung, Goyeong Choi, Kwang-Hyeon Liu |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
circadian rhythm endocrine system Circadian clock Pharmaceutical Science Article 03 medical and health sciences cryptochrome inhibitor Pharmacy and materia medica 0302 clinical medicine Cryptochrome Transcription (biology) Drug Discovery circadian clock Moiety Circadian rhythm Molecular clock Enhancer Chemistry bioisosteric replacement Small molecule RS1-441 030104 developmental biology Biochemistry Medicine Molecular Medicine 030217 neurology & neurosurgery |
| Zdroj: | Pharmaceuticals Volume 14 Issue 6 Pharmaceuticals, Vol 14, Iss 496, p 496 (2021) |
| ISSN: | 1424-8247 |
| DOI: | 10.3390/ph14060496 |
| Popis: | 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 attractive 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 replacement. 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. |
| Databáze: | OpenAIRE |
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