|
|
CCCCC1=NC2(CCCC2)C(=O)N1CC3=CC=C(C=C3)C4=CC=CC=C4C#N |
Approved |
|
Arntl (gene)
,
PER3
|
Angiotensin receptor binding,
PER3
|
Zhao, et al., 2024. Irbesartan ameliorates diabetic kidney injury in db/db mice by restoring circadian rhythm and cell cycle. Journal of translational internal medicine, 12(2), pp.157-169.
|
|
|
C1=CC=C2C(=C1)C=CC3=CC4=CC=CC=C4C=C32 |
None |
|
CRY1-PER2 complex
,
CLOCK-BMAL1
,
Arntl (gene)
|
Disruption of circadian clock,
Interferes with CLOCK–BMAL1,
aryl hydrocarbon receptor (AhR) binding
|
|
|
|
C1=CC=C2C(=C1)C=C3C=CC4=C5C3=C2C6=CC=CC=C6C5=CC=C4 |
none |
|
mPer2
,
mPer1
,
CRY1-PER2 complex
,
CRY1
,
CLOCK-BMAL1
,
Arntl (gene)
|
Disruption of circadian clock,
Core clock suppression,
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.
|
|
|
C1=CC=C2C=C3C=CC=CC3=CC2=C1 |
none |
|
CRY1-PER2 complex
,
CLOCK-BMAL1
|
Disruption of circadian clock,
Core clock suppression,
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.
|
|
|
C1=CC=C2C=CC=CC2=C1 |
none |
|
CLOCK-BMAL1
|
Core clock modulation,
Core clock suppression,
Bmal1,
BMAL1 expression modulation
|
Koh, Y.C. and Pan, M.H., 2024. Food-Borne Polycyclic Aromatic Hydrocarbons and Circadian Disruption. ACS omega, 9(29), pp.31298-31312.
|
|
|
CC1=C(C2=CC3=C(C(=C([N-]3)C=C4C(=C(C(=N4)C=C5C(=C(C(=N5)C=C1[N-]2)C)C=C)C)C=C)C)CCC(=O)O)CCC(=O)O.[Fe+2] |
Not approved |
|
CLOCK-BMAL1
|
Serves as a cofactor in various hemoproteins (e.g., hemoglobin, cytochromes) and can modulate transcription factors (e.g., REV-E
|
Freeman, S.L., Kwon, H., Portolano, N., Parkin, G., Venkatraman Girija, U., Basran, J., Fielding, A.J., Fairall, L., Svistunenko, D.A., Moody, P.C. and Schwabe, J.W., 2019. Heme binding to human CLOCK affects interactions with the E-box. Proceedings of the National Academy of Sciences, 116(40), pp.19911-19916.
|
|
|
COC1=CC(=CC(=C1)/C=C/C2=CC=C(C=C2)O)OC |
Not approved |
|
mPer2
,
mPer1
,
CRY1-PER2 complex
,
CRY1
,
CLOCK-BMAL1
,
Arntl (gene)
,
BMAL1 expression (induction)
|
Core clock modulation,
Bmal1,
de-repressing BMAL1,
BMAL1 expression modulation,
BMAL1 expression modulation,
Activation of CLOCK/Bmal1 mediated transcription,
SIRT1-mediated peroxisome proliferator-activated receptor coactivator 1α (PGC-1α) deacetylation in sleep-restricted mice
|
Liu, Y., Lang, H., Zhou, M., Huang, L., Hui, S., Wang, X., Chen, K. and Mi, M., 2020. The preventive effects of pterostilbene on the exercise intolerance and circadian misalignment of mice subjected to sleep restriction. Molecular Nutrition & Food Research, 64(11), p.1900991.
,
Zhang, J., Chang, M., Wang, X., Zhou, X., Bai, Q., Lang, H., Zhang, Q., Yi, L., Mi, M. and Chen, K., 2024. Pterostilbene targets the molecular oscillator RORγ to restore circadian rhythm oscillation and protect against sleep restriction induced metabolic disorders. Phytomedicine, 125, p.155327.
|
|
|
CCCCCNC(=O)N1CCC(C1)CN(CC2=CC=C(C=C2)Cl)CC3=CC=C(S3)[N+](=O)[O-] |
none |
|
mPer2
,
REV-ERBα
,
BMAL1 expression (induction)
,
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.
|
|
|
CC(C)(C)OC(=O)CN(CC1=CC=C(C=C1)Cl)CC2=CC=C(S2)[N+](=O)[O-] |
none |
|
REV-ERBα
|
Antagonist of Rev-Erb nuclear receptors
|
Grant, D., Yin, L., Collins, J.L., Parks, D.J., Orband-Miller, L.A., Wisely, G.B., Joshi, S., Lazar, M.A., Willson, T.M. and Zuercher, W.J., 2010. GSK4112, a small molecule chemical probe for the cell biology of the nuclear heme receptor Rev-erbα. ACS chemical biology, 5(10), pp.925-932.
|
|
|
CC(C1=CC(=C(C=C1)OC)OC)C(=O)C2=C(C=C(C=C2)C(C)(C)C#C)OC |
none |
|
CLOCK-BMAL1
|
Core clock modulation,
Bmal1,
BMAL1 expression modulation
|
Huang, S., Jiao, X., Lu, D., Pei, X., Qi, D. and Li, Z., 2020. Recent advances in modulators of circadian rhythms: an update and perspective. Journal of Enzyme Inhibition and Medicinal Chemistry, 35(1), pp.1267-1286.
|
|
|
C[C@@H]1[C@H]([C@H](C[C@@H](O1)O[C@@H]2[C@H](O[C@H](C[C@@H]2O)O[C@@H]3[C@H](O[C@H](C[C@@H]3O)O[C@H]4CC[C@]5([C@@H](C4)CC[C@@H]6[C@@H]5C[C@H]([C@]7([C@@]6(CC[C@@H]7C8=CC(=O)OC8)O)C)O)C)C)C)O)O |
Approved |
|
ROR gamma
|
ROR,
RORγ binding
|
Huh, J.R., Leung, M.W., Huang, P., Ryan, D.A., Krout, M.R., Malapaka, R.R., Chow, J., Manel, N., Ciofani, M., Kim, S.V. and Cuesta, A., 2011. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity. Nature, 472(7344), pp.486-490.
|
|
|
CC1=CC=C(C=C1)N2C(=O)N(C(=O)S2)CC3=CC=C(C=C3)F |
none |
|
ROR gamma
|
ROR,
RORγ binding
|
Zhang, W., Zhang, J., Fang, L., Zhou, L., Wang, S., Xiang, Z., Li, Y., Wisely, B., Zhang, G., An, G. and Wang, Y., 2012. Increasing human Th17 differentiation through activation of orphan nuclear receptor retinoid acid-related orphan receptor γ (RORγ) by a class of aryl amide compounds. Molecular pharmacology, 82(4), pp.583-590.
,
Trebucq, L.L., Cardama, G.A., Lorenzano Menna, P., Golombek, D.A., Chiesa, J.J. and Marpegan, L., 2021. Timing of novel drug 1A-116 to circadian rhythms improves therapeutic effects against glioblastoma. Pharmaceutics, 13(7), p.1091.
|
|
|
C[C@H]1[C@H]2[C@H](C[C@@H]3[C@@]2(CC[C@H]4[C@H]3CC=C5[C@@]4([C@@H](C[C@@H](C5)O)O)C)C)O[C@]16CCC(=C)CO6 |
none |
|
RORA
,
RORα
,
NR1F1
|
ROR
|
Helleboid, S., Haug, C., Lamottke, K., Zhou, Y., Wei, J., Daix, S., Cambula, L., Rigou, G., Hum, D.W. and Walczak, R., 2014. The identification of naturally occurring neoruscogenin as a bioavailable, potent, and high-affinity agonist of the nuclear receptor RORα (NR1F1). Journal of biomolecular screening, 19(3), pp.399-406.
|
|
|
COC1=C(C=C(C=C1)C2=CC(=O)C3=C(O2)C(=C(C(=C3OC)OC)OC)OC)OC |
Not approved |
prolonged period, increased amplitude, and phase modulation
|
RORA
|
Core clock modulation,
ROR,
PER gene exspression modulation,
Activation of CLOCK/Bmal1 mediated transcription
|
Lellupitiyage Don, S.S., Robertson, K.L., Lin, H.H., Labriola, C., Harrington, M.E., Taylor, S.R. and Farkas, M.E., 2020. Nobiletin affects circadian rhythms and oncogenic characteristics in a cell-dependent manner. PLoS One, 15(7), p.e0236315.
,
Ryan, C., Tahara, Y., Haraguchi, A., Lu, Y. and Shibata, S., 2024. Nobiletin stimulates adrenal hormones and modulates the circadian clock in mice. Nutrients, 16(10), p.1491.
,
Neba Ambe, G.N., Breda, C., Bhambra, A.S. and Arroo, R.R., 2022. Effect of the citrus flavone nobiletin on circadian rhythms and metabolic syndrome. Molecules, 27(22), p.7727.
,
Lellupitiyage Don, S.S., Robertson, K.L., Lin, H.H., Labriola, C., Harrington, M.E., Taylor, S.R. and Farkas, M.E., 2020. Nobiletin affects circadian rhythms and oncogenic characteristics in a cell-dependent manner. PLoS One, 15(7), p.e0236315.
,
Martchenko, A., Biancolin, A.D., Martchenko, S.E. and Brubaker, P.L., 2022. Nobiletin ameliorates high fat-induced disruptions in rhythmic glucagon-like peptide-1 secretion. Scientific Reports, 12(1), p.7271.
|
|
|
C1=CC=C(C=C1)C(C2=CC=CC=C2)C(=O)NC(CCCN=C(N)N)C(=O)NCC3=CC=C(C=C3)O |
Not approved |
|
Neuropeptide Y Y1 receptor
|
Neuropeptide Y1 receptor binding
|
Sautel, M., Rudolf, K., Wittneben, H., Herzog, H., Martinez, R., Munoz, M., Eberlein, W., Engel, W., Walker, P. and Beck-Sickinger, A.G., 1996. Neuropeptide Y and the nonpeptide antagonist BIBP 3226 share an overlapping binding site at the human Y1 receptor. Molecular pharmacology, 50(2), pp.285-292.
|
|
|
CCC1=CC=C(C=C1)N(CC(C)C)S(=O)(=O)C2=CC(=C(C=C2)OCC3CCOCC3)CO |
none |
|
ROR gamma
|
ROR,
RORγ binding
|
Amaudrut, J., Argiriadi, M.A., Barth, M., Breinlinger, E.C., Bressac, D., Broqua, P., Calderwood, D.J., Chatar, M., Cusack, K.P., Gauld, S.B. and Jacquet, S., 2019. Discovery of novel quinoline sulphonamide derivatives as potent, selective and orally active RORγ inverse agonists. Bioorganic & Medicinal Chemistry Letters, 29(14), pp.1799-1806.
|
|
|
CC(C)NCCN(C(C)C)S(=O)(=O)C1=C(C=C(C=C1)Cl)Cl |
Not approved |
Affects melatonin synthsis
|
TRPV4 Channel
|
This inhibition of TRPV4-mediated signaling can affect downstream pathways involved in the regulation of the circadian clock.
|
Alkozi, H.A., de Lara, M.J.P. and Pintor, J., 2017. Melatonin synthesis in the human ciliary body triggered by TRPV4 activation: Involvement of AANAT phosphorylation. Experimental eye research, 162, pp.1-8.
|
|
|
CC(=O)N1CC2=C([C@@H]1C(=O)NC3=CC=C(C=C3)C(C(F)(F)F)(C(F)(F)F)O)C=CC(=C2)S(=O)(=O)C |
None |
|
ROR gamma
|
ROR,
RORγ binding
|
Ribeiro, R.F., Cavadas, C. and Silva, M.M.C., 2021. Small-molecule modulators of the circadian clock: Pharmacological potentials in circadian-related diseases. Drug Discovery Today, 26(7), pp.1620-1641.
|
|
|
COC1=C(C=C2CC(C(=O)C2=C1)CC3=C(C=CC=N3)C(F)(F)F)N4CCOCC4 |
None |
|
ROR gamma
|
ROR
|
Ribeiro, R.F., Cavadas, C. and Silva, M.M.C., 2021. Small-molecule modulators of the circadian clock: Pharmacological potentials in circadian-related diseases. Drug Discovery Today, 26(7), pp.1620-1641.
|
|
|
CCS(=O)(=O)C1=CN=C(C=C1)CNC(=O)C2=CC3=C([C@H](N(C3)CC4CCC(CC4)C(F)(F)F)C(C)C)N=C2 |
Not approved |
|
ROR gamma
|
RORyt/RORc inhibitor
|
Ribeiro, R.F., Cavadas, C. and Silva, M.M.C., 2021. Small-molecule modulators of the circadian clock: Pharmacological potentials in circadian-related diseases. Drug Discovery Today, 26(7), pp.1620-1641.
,
Liu, S., Liu, D., Shen, R., Li, D., Hu, Q., Yan, Y., Sun, J., Zhang, F., Wan, H., Dong, P. and Feng, J., 2021. Discovery of a novel RORγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis. Scientific Reports, 11(1), p.9132.
|
|
|
CC(C)N1C=NC2=C1N=CN=C2N(CC3=CC(=CC=C3)C(F)(F)F)CC4=C(C=CC=C4)[N+](=O)[O-] |
None |
|
CKI delta
|
Inhibits CKIδ
|
|
|
|
C1COCCC1N2C3=NC=NC(=C3C(=N2)COC4=CC(=CC=C4)Cl)N |
Not approved |
|
CK1δ
|
CK1 Inhibition
|
|
|
|
CC1=CC2=C(C=C1Cl)N=C(S2)NC(=O)CC3=CC=CC=C 3 |
None |
|
CKI delta
|
Inhibits casein kinase 1 delta (CKIδ) activity,
Inhibits CKIδ
|
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.
|
|
|
C1=CC(=CC(=C1)Cl)NC2=NC3=C(C=CC(=C3)C(=O)O)C4=C2C=CN=C4 |
Not approved |
|
CK1δ
|
Binds to the ATP‑binding site of CK2
|
Siddiqui-Jain, A., Drygin, D., Streiner, N., Chua, P., Pierre, F., O'Brien, S.E., Bliesath, J., Omori, M., Huser, N., Ho, C. and Proffitt, C., 2010. CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer research, 70(24), pp.10288-10298.
|
|
|
COC1=CC(=C(CN(C2=C3N=CN(C3=NC=N2)C(C)C)CC2=CC(=CC=C2)C(F)(F)F)C=C1OC)[N+](=O)[O-] |
none |
|
CKI delta
|
Inhibits casein kinase 1 delta (CKIδ) activity,
Inhibits CKIδ
|
Kolarski, D., Sugiyama, A., Breton, G., Rakers, C., Ono, D., Schulte, A., Tama, F., Itami, K., Szymanski, W., Hirota, T. and Feringa, B.L., 2019. Controlling the circadian clock with high temporal resolution through photodosing. Journal of the American Chemical Society, 141(40), pp.15784-15791.
|