|
|
CC1C=CC=C(C(=O)NC2=C(C3=C(C4=C(C(=C3O)C)OC(C4=O)(OC=CC(C(C(C(C(C(C1O)C)O)C)OC(=O)C)C)OC)C)C5=C2N6C=CC(=CC6=N5)C)O)C |
Approved |
protective effects against cognitive impairment caused by circadian rhythm disruption
|
Microbiota
|
protect
|
Meng, D., Yang, M., Hu, L., Liu, T., Zhang, H., Sun, X., Wang, X., Chen, Y.U., Jin, Y.U. and Liu, R., 2022. Rifaximin protects against circadian rhythm disruption–induced cognitive impairment through preventing gut barrier damage and neuroinflammation. Journal of neurochemistry, 163(5), pp.406-418.
|
|
|
CCOC(=O)N1CCC(C1)CN(CC2=CC=C(C=C2)Cl)CC3=CC=C(S3)[N+](=O)[O-] |
not approved |
Phase stabilization and circadian gene modulation in mice
|
mPer2
,
REV-ERBα
,
Per2 expression
|
Agonist REV-ERB alpha
|
Solt, L.A., et al, 2012. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature, 485(7396), pp.62-68.
,
Yang, M.Y., Lin, H.Y.H., Chen, Y.Y.M., Hu, M.L., Chen, I.Y. and Yang, C.H., 2025. Chronic low-dose REV-ERBs agonist SR9009 mitigates constant light-induced weight gain and insulin resistance via adipogenesis modulation. Biomedical Journal, p.100830.
|
|
|
C1CCC2(C1)CC(=O)N(C(=O)C2)CCCCN3CCN(CC3)C4=NC=CC=N4 |
Approved |
Phase advance and reduced amplitude in mice and hamsters
|
5-HT1A
|
Serotoninergic signaling
|
Smith, V.M., Iannatonne, S., Achal, S., Jeffers, R.T. and Antle, M.C., 2014. The serotonergic anxiolytic buspirone attenuates circadian responses to light. European Journal of Neuroscience, 40(10), pp.3512-3525.
|
|
|
C1=CC=C2C(=C1)C3=C4C2=CC5=CC=CC6=C5C4=C(C=C6)C=C3 |
none |
Circadian rhythm disruption in mammals
|
CLOCK-BMAL1
|
Disruption of circadian clock,
aryl hydrocarbon receptor (AhR) binding
|
Koh, Y.C. and Pan, M.H., 2024. Food-Borne Polycyclic Aromatic Hydrocarbons and Circadian Disruption. ACS omega, 9(29), pp.31298-31312.
|
|
|
CN1CCN(CC1)CCCN2C3=CC=CC=C3SC4=C2C=C(C=C4)C(F)(F)F |
Approved |
Phase shift in fungi (Neurospora)
|
Calmodulin
|
Calmodulin binding (Neurospora)
|
Suzuki, S., Katagiri, S. and Nakashima, H., 1996. Mutants with altered sensitivity to a calmodulin antagonist affect the circadian clock in Neurospora crassa. Genetics, 143(3), pp.1175-1180.
|
|
|
CCOC(=O)C1CC2=CC=CC=C2CN1C(=O)C3=CC=C(S3)SC |
Not approved |
Amplitude enhancement and phase shift in human cells
|
CLOCK-BMAL1
|
Antagonist of Rev-Erb nuclear receptors,
de-repressing BMAL1
|
Kojetin, D., Wang, Y., Kamenecka, T.M. and Burris, T.P., 2011. Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB. ACS chemical biology, 6(2), pp.131-134.
,
Anabtawi, N., Cvammen, W. and Kemp, M.G., 2021. Pharmacological inhibition of cryptochrome and REV-ERB promotes DNA repair and cell cycle arrest in cisplatin-treated human cells. Scientific Reports, 11(1), p.17997.
|
|
|
C1=CC2=C3C(=C1)C4=CC=CC5=C4C6=C(C=C5)C=CC(=C36)C=C2 |
None |
Circadian rhythm disruption in mammals
|
mPer2
,
mPer1
,
CRY1-PER2 complex
,
CLOCK-BMAL1
|
Disruption of circadian clock,
Interferes with CLOCK–BMAL1,
aryl hydrocarbon receptor (AhR) binding
|
Koh, Y.C. and Pan, M.H., 2024. Food-Borne Polycyclic Aromatic Hydrocarbons and Circadian Disruption. ACS omega, 9(29), pp.31298-31312.
|
|
|
CN(C)CCCN1C2=CC=CC=C2SC3=CC=CC=C31 |
Approved |
Circadian rhythm disruption in humans
|
D2R (dopamine receptor)
|
Hypnotic effect,
Sleep promotion
|
Nagayama, H., Takagi, A., Sakurai, Y., Nishiwaki, K. and Takahashi, R., 1978. Chronopharmacological study of neuroleptics: II. Circadian susceptibility rhythm to chlorpromazine. Psychopharmacology, 58, pp.49-53.
|
|
|
CC1=C(OC2=C1C3=C(C=C2)OC(CC3=O)(C)C4=CC=C(C=C4)Cl)C(=O)N5CCC6=CC=CC=C65 |
Not approved |
Period lengthening in human cells (U2OS)
|
CRY1
|
Binds CRY1 FAD-binding
|
Gul, S., Akyel, Y.K., Gul, Z.M., Isin, S., Ozcan, O., Korkmaz, T., Selvi, S., Danis, I., Ipek, O.S., Aygenli, F. and Taskin, A.C., 2022. Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice. Nature Communications, 13(1), p.6742.
|
|
|
C1=CC=C2C(=C1)C=CC3=CC4=C(C=CC5=CC=CC=C54)C=C32 |
none |
Circadian disruption via core clock interference (in mammals)
|
mPer2
,
mPer1
,
CRY1-PER2 complex
,
CLOCK-BMAL1
|
Disruption of circadian clock,
Bmal1,
Interferes with CLOCK–BMAL1,
aryl hydrocarbon receptor (AhR) binding
|
Koh, Y.C. and Pan, M.H., 2024. Food-Borne Polycyclic Aromatic Hydrocarbons and Circadian Disruption. ACS omega, 9(29), pp.31298-31312.
|
|
|
C1CN(CCC1N2C3=CC=CC=C3NC2=O)CCCC(C4=CC=C(C=C4)F)C5=CC=C(C=C5)F |
Approved |
Phase-dependent modulation of activity amplitude and onset (in rodents)
|
D2R (dopamine receptor)
|
Dopamine receptor binding
|
Davies, J.A., 1979. The Influence of Dopaminergic Mechanism on 24-Hour Temperature and Activity Rhythms in Rodents. In Neuro-Psychopharmacology (pp. 611-620). Pergamon.
|
|
|
C1CCC(CC1)N2C=NC(=C2C3=NC(=NC=C3)N)C4=CC=C(C=C4)F.Cl.Cl |
Not approved |
Period lengthening and phase delay in rodents and SCN slices
|
CK1δ
|
Inhibits CK1δ
|
Meng, Q.J., Maywood, E.S., Bechtold, D.A., Lu, W.Q., Li, J., Gibbs, J.E., Dupré, S.M., Chesham, J.E., Rajamohan, F., Knafels, J. and Sneed, B., 2010. Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes. Proceedings of the National Academy of Sciences, 107(34), pp.15240-15245.
|
|
|
C1=CC=C2C(=C1)C=CC3=C2C=CC4=CC=CC=C43 |
none |
Circadian disruption via core clock targeting in mammals
|
mPer2
,
mPer1
,
CRY1-PER2 complex
,
CRY1
,
CLOCK-BMAL1
|
Disruption of circadian clock,
Bmal1,
modulation of nuclear receptor signaling pathways,
Interferes with CLOCK–BMAL1,
Targets BMAL1–CLOCK DNA-binding activity
|
Koh, Y.C. and Pan, M.H., 2024. Food-Borne Polycyclic Aromatic Hydrocarbons and Circadian Disruption. ACS omega, 9(29), pp.31298-31312.
|
|
|
C1CCC(C(C1)CN2CCN(CC2)C3=NSC4=CC=CC=C43)CN5C(=O)C6C7CCC(C7)C6C5=O |
Approved |
Clock gene normalization and potential phase shift in rats
|
mPer2
,
mPer1
,
CRY1-PER2 complex
,
CRY1
,
CLOCK-BMAL1
,
Arntl (gene)
|
Core clock modulation
|
Calabrese, F., Savino, E., Papp, M., Molteni, R. and Riva, M.A., 2016. Chronic mild stress-induced alterations of clock gene expression in rat prefrontal cortex: modulatory effects of prolonged lurasidone treatment. Pharmacological research, 104, pp.140-150.
,
Krystal, A.D. and Zammit, G., 2016. The sleep effects of lurasidone: a placebo‐controlled cross‐over study using a 4‐h phase‐advance model of transient insomnia. Human Psychopharmacology: Clinical and Experimental, 31(3), pp.206-216.
|
|
|
C1=CC=C2C=C3C4=CC=CC5=C4C(=CC=C5)C3=CC2=C1 |
none |
Circadian disruption via core clock gene targeting in animals (PAH exposure model)
|
mPer2
,
mPer1
,
CRY1-PER2 complex
,
CRY1
,
CLOCK-BMAL1
|
Disruption of circadian clock,
Bmal1,
Interferes with CLOCK–BMAL1,
Targets BMAL1–CLOCK DNA-binding activity,
aryl hydrocarbon receptor (AhR) binding
|
Koh, Y.C. and Pan, M.H., 2024. Food-Borne Polycyclic Aromatic Hydrocarbons and Circadian Disruption. ACS omega, 9(29), pp.31298-31312.
|
|
|
C1CN(CCN1CCC=C2C3=CC=CC=C3SC4=C2C=C(C=C4)C(F)(F)F)CCO |
Approved |
Circadian disruption in humans (rest-activity rhythm disturbance with flupentixol)
|
Unknown
|
Unknown,
5-HT7 binding
|
Dagan, Y. and Borodkin, K., 2005. Behavioral and psychiatric consequences of sleep-wake schedule disorders. Dialogues in clinical neuroscience, 7(4), pp.357-365.
,
Bad News for Antipsychotics and Circadian Rhythms
|
|
|
CCCCCC1=CC(=C2C(=C1)OC(C3=C2C=C(C=C3)C)(C)C)O |
Not approved |
Circadian modulation potential via CB2 in mammals (indirect, immune-related pathways)
|
Cannabinoid receptor
,
CB2
|
Disruption of circadian clock,
Core clock modulation,
Unknown,
Cannabinoid receptor stimulation
|
Lafaye G, Desterke C, Marulaz L, Benyamina A. Cannabidiol affects circadian clock core complex and its regulation in microglia cells. Addiction Biology. 2018.
|
|
|
CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC=CC=N3 |
Approved |
restores normal circadian rhythms,
shifted the phases
|
T58921 Peroxisome proliferator-activated receptor gamma (PPAR-gamma)
,
BMAL1 expression (induction)
,
CLOCK gene expression
|
protect
|
Tian, Y., Luan, X. and Yang, K., 2024. Chronotherapy involving rosiglitazone regulates the phenotypic switch of vascular smooth muscle cells by shifting the phase of TNF-α rhythm through triglyceride accumulation in macrophages. Heliyon, 10(10), p.e30708.
,
Tian, Y., Luan, X. and Yang, K., 2024. Chronotherapy involving rosiglitazone regulates the phenotypic switch of vascular smooth muscle cells by shifting the phase of TNF-α rhythm through triglyceride accumulation in macrophages. Heliyon, 10(10), p.e30708.
|
|
|
CC1=CC2=C(C=C1Cl)N=C(S2)NC(=O)CC3=CC=CC=C3 |
Not approved |
Period lengthening in human cells (U2OS)
|
CK1δ
|
Inhibits casein kinase 1 delta (CKIδ) activity
|
Lee, J.W., Hirota, T., Peters, E.C., Garcia, M., Gonzalez, R., Cho, C.Y., Wu, X., Schultz, P.G. and Kay, S.A., 2011. A small molecule modulates circadian rhythms through phosphorylation of the period protein. Angewandte Chemie (International ed. in English), 50(45), p.10608.
,
Ray, S., Lach, R., Heesom, K.J., Valekunja, U.K., Encheva, V., Snijders, A.P. and Reddy, A.B., 2019. Phenotypic proteomic profiling identifies a landscape of targets for circadian clock–modulating compounds. Life Science Alliance, 2(6).
|
|
|
[2H]C([2H])([2H])C(=O)NCCC1=CC=CC2=C1C=C(C=C2)OC |
Approved |
Phase shifting in humans (via MT1/MT2 receptor activation)
|
Melatonin receptor
|
Melatonin receptor binding
|
Russak, E.M. and Bednarczyk, E.M., 2019. Impact of deuterium substitution on the pharmacokinetics of pharmaceuticals. Annals of Pharmacotherapy, 53(2), pp.211–216.
,
Audinot, V., Mailliet, F., Lahaye-Brasseur, C., Bonnaud, A., Le Gall, A., Amossé, C., Dromaint, S., Rodriguez, M., Nagel, N., Galizzi, J.P., Malpaux, B., Guillaumet, G., Lesieur, D., Lefoulon, F., Renard, P., Delagrange, P. and Boutin, J.A., 2003. New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn-Schmiedeberg's Archives of Pharmacology, 367(6), pp.553–561.
|
|
|
C1=CC(=O)C2=NC=CN=C2C1=O |
Not approved |
Transcriptional inhibition of BMAL1–CLOCK complex in human cells
|
CLOCK-BMAL1
|
Targets BMAL1–CLOCK DNA-binding activity
|
Hosoya, Y., Nojo, W., Kii, I., Suzuki, T., Imanishi, M. and Ohkanda, J., 2020. Identification of synthetic inhibitors for the DNA binding of intrinsically disordered circadian clock transcription factors. Chemical Communications, 56(76), pp.11203-11206.
|
|
|
C1=CC(=CC=C1C(=O)NC2=CC=C(C=C2)C(C(F)(F)F)(C(F)(F)F)O)C(F)(F)F |
Not approved |
It affects circadian rhythms by activating RORα/γ, which in turn regulates the transcription of target genes, including the core clock component BMAL1
|
RORα
|
ROR
|
Wang, Y., Kumar, N., Nuhant, P., Cameron, M.D., Istrate, M.A., Roush, W.R., Griffin, P.R. and Burris, T.P., 2010. Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ. ACS chemical biology, 5(11), pp.1029-1034.
,
Wang, Y., Kumar, N., Nuhant, P., Cameron, M. D., Istrate, M. A., Roush, W. R., Griffin, P. R., & Burris, T. P. (2010). Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ. ACS Chemical Biology, 5(11), 1029–1034
|
|
|
CC1=CN=C(N1)C2=CN=C(N=C2C3=C(C=C(C=C3)Cl)Cl)NCCNC4=NC=C(C=C4)C# N |
none |
disrupts glioblastoma clock,
Per2 disruption affected both GBM migration and cell cycle progression.
|
GSK-3α/β
|
Highly selective, ATP-competitive inhibition of GSK-3 (both α and β isoforms),
GSK‑3 Inhibition,
Selective GSK-3β Inhibition:,
inhibits glycogen synthase kinase-3β (GSK-3β)
|
Wagner, P.M., Fornasier, S.J. and Guido, M.E., 2024. Pharmacological modulation of the cytosolic oscillator affects glioblastoma cell biology. Cellular and Molecular Neurobiology, 44(1), p.51.
|
|
|
CN1C2CCC1C(C(C2)OC(=O)C3=CC=CC=C3)C(=O)OC |
Not approved |
inhibition of photic phase shifts in mice (SCN-dependent)
|
SEROTONIN TRANSPORTER
,
PPAR gamma
,
D2R (dopamine receptor)
|
Core clock modulation,
Unknown,
Dopamine receptor binding
|
Prosser, R.A., Stowie, A., Amicarelli, M., Nackenoff, A.G., Blakely, R.D. and Glass, J.D., 2014. Cocaine modulates mammalian circadian clock timing by decreasing serotonin transport in the SCN. Neuroscience, 275, pp.184–193
,
Wang, D.Q., Wang, X.L., Wang, C.Y., Wang, Y., Li, S.X. and Liu, K.Z., 2019. Effects of chronic cocaine exposure on the circadian rhythmic expression of the clock genes in reward-related brain areas in rats. Behavioural Brain Research, 363, pp.61–69.
|
|
|
CCOC(CC1=CC(=CC=C1)C(=NOCC2=CC=C(C=C2)Br)C)C(=O)O |
Not approved |
CRY1/2 inhibition,
decreased the amplitude of circadian rhythm significantly while having no effect on the period
|
CRY1-PER2 complex
,
CRY1
,
CRY2
|
Binds CRY1 FAD-binding,
CRY1/2 inhibitor,
Activation of CLOCK/Bmal1 mediated transcription
|
Chun, S.K., Jang, J., Chung, S., Yun, H., Kim, N.J., Jung, J.W., Son, G.H., Suh, Y.G. and Kim, K., 2014. Identification and validation of cryptochrome inhibitors that modulate the molecular circadian clock. ACS chemical biology, 9(3), pp.703-710.
,
전승국, 2014. Development of circadian clock modulator and its application (Doctoral dissertation, 서울대학교 대학원).
,
Jang, J., Chung, S., Choi, Y., Lim, H.Y., Son, Y., Chun, S.K., Son, G.H., Kim, K., Suh, Y.G. and Jung, J.W., 2018. The cryptochrome inhibitor KS15 enhances E-box-mediated transcription by disrupting the feedback action of a circadian transcription-repressor complex. Life sciences, 200, pp.49-55.
,
Solovev, I.A., Shaposhnikov, M.V. and Moskalev, A.A., 2021. Chronobiotics KL001 and KS15 extend lifespan and modify circadian rhythms of Drosophila melanogaster. Clocks & Sleep, 3(3), pp.429-441.
|