SAFit2

SAFit2
Legal status
Legal status	US: Investigational drug;
Identifiers
	IUPAC name [(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	1643125-33-0;
PubChem CID	86277887;
ChemSpider	32779480;
ChEMBL	ChEMBL3623630;
Chemical and physical data
Formula	C46H62N2O10
Molar mass	803.006 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES 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 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.

References[edit]

^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.

[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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