SAFit2

Last updated
SAFit2
SAFit2 structure.png
Legal status
Legal status
  • US:Investigational drug
Identifiers
  • [(1R)-3-(3,4-dimethoxyphenyl)-1-[3-(2-morpholin-4-ylethoxy)phenyl]propyl] (2S)-1-[(2S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl]piperidine-2-carboxylate
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
Formula C46H62N2O10
Molar mass 803.006 g·mol−1
3D model (JSmol)
  • COC1=C(C=C(C=C1)CC[C@H](C2=CC(=CC=C2)OCCN3CCOCC3)OC(=O)[C@@H]4CCCCN4C(=O)[C@@H](C5CCCCC5)C6=CC(=C(C(=C6)OC)OC)OC)OC
  • InChI=1S/C46H62N2O10/c1-51-39-20-18-32(28-40(39)52-2)17-19-38(34-14-11-15-36(29-34)57-27-24-47-22-25-56-26-23-47)58-46(50)37-16-9-10-21-48(37)45(49)43(33-12-7-6-8-13-33)35-30-41(53-3)44(55-5)42(31-35)54-4/h11,14-15,18,20,28-31,33,37-38,43H,6-10,12-13,16-17,19,21-27H2,1-5H3/t37-,38+,43-/m0/s1
  • Key:ZDBWLRLGUBSLPG-FDHYQTMZSA-N

SAFit2 is a drug which acts as a potent and selective inhibitor of the signalling factor FK506 binding protein 51 (FKBP51), which is involved in the downstream response to glucocorticoid release in the body. [1] Since elevated glucocorticoid levels are a characteristic marker of chronic stress, blocking glucocorticoid signalling pathways using SAFit2 has been shown to counteract many of the associated symptoms such as obesity, [2] [3] chronic pain, [4] [5] depression and anxiety, [6] [7] and addiction. [8] [9] While SAFit2 itself is a relatively large molecule and is unlikely to have suitable properties to be developed for medical use, it has demonstrated that inhibition of FKBP51 may be a useful therapeutic approach for alleviating consequences of long-term chronic stress and pain.

See also

References

  1. ↑ Gaali S, Kirschner A, Cuboni S, Hartmann J, Kozany C, Balsevich G, et al. (January 2015). "Selective inhibitors of the FK506-binding protein 51 by induced fit". Nature Chemical Biology. 11 (1): 33–7. doi:10.1038/nchembio.1699. PMID   25436518.
  2. ↑ Balsevich G, Häusl AS, Meyer CW, Karamihalev S, Feng X, Pöhlmann ML, et al. (November 2017). "Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function". Nature Communications. 8 (1) 1725. Bibcode:2017NatCo...8.1725B. doi:10.1038/s41467-017-01783-y. PMC   5700978 . PMID   29170369.
  3. ↑ Häusl AS, Balsevich G, Gassen NC, Schmidt MV (November 2019). "Focus on FKBP51: A molecular link between stress and metabolic disorders". Molecular Metabolism. 29: 170–181. doi:10.1016/j.molmet.2019.09.003. PMC   6812026 . PMID   31668388.
  4. ↑ Maiarù M, Tochiki KK, Cox MB, Annan LV, Bell CG, Feng X, et al. (February 2016). "The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling". Science Translational Medicine. 8 (325): 325ra19. doi:10.1126/scitranslmed.aab3376. PMC   4880036 . PMID   26865567.
  5. ↑ Maiarù M, Morgan OB, Mao T, Breitsamer M, Bamber H, Pöhlmann M, et al. (July 2018). "The stress regulator FKBP51: a novel and promising druggable target for the treatment of persistent pain states across sexes". Pain. 159 (7): 1224–1234. doi:10.1097/j.pain.0000000000001204. PMC   6012049 . PMID   29533388.
  6. ↑ Hartmann J, Wagner KV, Gaali S, Kirschner A, Kozany C, Rühter G, et al. (June 2015). "Pharmacological Inhibition of the Psychiatric Risk Factor FKBP51 Has Anxiolytic Properties". The Journal of Neuroscience. 35 (24): 9007–16. doi:10.1523/JNEUROSCI.4024-14.2015. PMC   6605153 . PMID   26085626.
  7. ↑ Pöhlmann ML, Häusl AS, Harbich D, Balsevich G, Engelhardt C, Feng X, et al. (2018). "Pharmacological Modulation of the Psychiatric Risk Factor FKBP51 Alters Efficiency of Common Antidepressant Drugs". Frontiers in Behavioral Neuroscience. 12 262. doi: 10.3389/fnbeh.2018.00262 . PMC   6240676 . PMID   30483074.
  8. ↑ König L, Kalinichenko LS, Huber SE, Voll AM, Bauder M, Kornhuber J, et al. (May 2020). "The selective FKBP51 inhibitor SAFit2 reduces alcohol consumption and reinstatement of conditioned alcohol effects in mice". Addiction Biology. 25 (3) e12758. doi:10.1111/adb.12758. PMID   31173432. S2CID   174811590.
  9. ↑ Savarese AM, Ozburn AR, Metten P, Schlumbohm JP, Hack WR, LeMoine K, et al. (March 2020). "Targeting the Glucocorticoid Receptor Reduces Binge-Like Drinking in High Drinking in the Dark (HDID-1) Mice". Alcoholism: Clinical and Experimental Research. 44 (5): 1025–1036. doi:10.1111/acer.14318. PMC   7211124 . PMID   32154593.
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