Resatorvid
{{Short description|Chemical compound}}
{{Drugbox
| IUPAC_name = ethyl (6R)-6-[(2-chloro-4-fluorophenyl)sulfamoyl]cyclohexene-1-carboxylate
| image = Resatorvid_structure.png
| image_class = skin-invert-image
| tradename = Resatorvid
| legal_US =
| legal_status =
| bioavailability =
| metabolism =
| elimination_half-life =
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| CAS_number = 243984-11-4
| PubChem = 11703255
| UNII = H2MZ648C31
| ChemSpiderID = 9877978
| ChEMBL = 225157
| DrugBank = 05943
| C=15 | H=17 | Cl=1 | F=1 | N=1 | O=4 | S=1
| SMILES = CCOC(=O)C1=CCCC[C@H]1S(=O)(=O)NC2=C(C=C(C=C2)F)Cl
| StdInChI=1S/C15H17ClFNO4S/c1-2-22-15(19)11-5-3-4-6-14(11)23(20,21)18-13-8-7-10(17)9-12(13)16/h5,7-9,14,18H,2-4,6H2,1H3/t14-/m1/s1
| StdInChIKey = LEEIJTHMHDMWLJ-CQSZACIVSA-N
}}
Resatorvid (TAK-242) is a cyclohexane derivative that was invented by scientists at Takeda in a drug discovery campaign to identify inhibitors of the receptor TLR4.{{cite journal | vauthors = Wang X, Smith C, Yin H | title = Targeting Toll-like receptors with small molecule agents | journal = Chemical Society Reviews | volume = 42 | issue = 12 | pages = 4859–4866 | date = June 2013 | pmid = 23503527 | pmc = 3665707 | doi = 10.1039/c3cs60039d }} It binds directly to cysteine residue 747 intracellularly, preventing TLR4 binding with TIRAP and thus preventing downstream signal transduction.{{cite journal | vauthors = Karimy JK, Reeves BC, Kahle KT | title = Targeting TLR4-dependent inflammation in post-hemorrhagic brain injury | journal = Expert Opinion on Therapeutic Targets | volume = 24 | issue = 6 | pages = 525–533 | date = June 2020 | pmid = 32249624 | pmc = 8104018 | doi = 10.1080/14728222.2020.1752182 }}
A randomized, double-blinded Phase III trial of resatorvid in sepsis was halted early due to lack of efficacy, and the compound has become a widely used tool compound in biological research.
It has antiinflammatory and neuroprotective effects in preclinical models.{{cite journal | vauthors = Miller S, Blanco MJ | title = Small molecule therapeutics for neuroinflammation-mediated neurodegenerative disorders | journal = RSC Medicinal Chemistry | volume = 12 | issue = 6 | pages = 871–886 | date = June 2021 | pmid = 34223157 | pmc = 8221257 | doi = 10.1039/d1md00036e }} It has been explored in preclinical studies of several forms of cancer, including multiple myeloma, breast cancer, and ovarian cancer,{{cite journal | vauthors = Innao V, Rizzo V, Allegra AG, Musolino C, Allegra A | title = Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma | journal = Cells | volume = 10 | issue = 2 | page = 439 | date = February 2021 | pmid = 33669515 | pmc = 7922387 | doi = 10.3390/cells10020439 | doi-access = free }} and has been suggested for study in skin cancers.{{cite journal | vauthors = Dickinson SE, Wondrak GT | title = TLR4-directed Molecular Strategies Targeting Skin Photodamage and Carcinogenesis | journal = Current Medicinal Chemistry | volume = 25 | issue = 40 | pages = 5487–5502 | date = 2018 | pmid = 28847267 | doi = 10.2174/0929867324666170828125328 | s2cid = 670318 }}
Efforts have been made to improve resatorvid by making prodrugs and deuterated derivatives.
See also
References
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Further reading
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- {{cite journal | vauthors = Matsunaga N, Tsuchimori N, Matsumoto T, Ii M | title = TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules | journal = Molecular Pharmacology | volume = 79 | issue = 1 | pages = 34–41 | date = January 2011 | pmid = 20881006 | doi = 10.1124/mol.110.068064 | s2cid = 7818996 }}
- {{cite journal | vauthors = Samarpita S, Kim JY, Rasool MK, Kim KS | title = Investigation of toll-like receptor (TLR) 4 inhibitor TAK-242 as a new potential anti-rheumatoid arthritis drug | journal = Arthritis Research & Therapy | volume = 22 | issue = 1 | pages = 16 | date = January 2020 | pmid = 31973752 | pmc = 6979396 | doi = 10.1186/s13075-020-2097-2 | doi-access = free }}
- {{cite journal | vauthors = Feng Y, Gao J, Cui Y, Li M, Li R, Cui C, Cui J | title = Neuroprotective Effects of Resatorvid Against Traumatic Brain Injury in Rat: Involvement of Neuronal Autophagy and TLR4 Signaling Pathway | journal = Cellular and Molecular Neurobiology | volume = 37 | issue = 1 | pages = 155–168 | date = January 2017 | pmid = 26961544 | doi = 10.1007/s10571-016-0356-1 | s2cid = 21583205 | pmc = 11482083 }}
- {{cite journal | vauthors = Dickinson SE, Wondrak GT | title = TLR4-directed Molecular Strategies Targeting Skin Photodamage and Carcinogenesis | journal = Current Medicinal Chemistry | volume = 25 | issue = 40 | pages = 5487–5502 | year = 2019 | pmid = 28847267 | doi = 10.2174/0929867324666170828125328 | s2cid = 670318 }}
- {{cite journal | vauthors = Kashani B, Zandi Z, Karimzadeh MR, Bashash D, Nasrollahzadeh A, Ghaffari SH | title = Blockade of TLR4 using TAK-242 (resatorvid) enhances anti-cancer effects of chemotherapeutic agents: a novel synergistic approach for breast and ovarian cancers | journal = Immunologic Research | volume = 67 | issue = 6 | pages = 505–516 | date = December 2019 | pmid = 32026322 | doi = 10.1007/s12026-019-09113-8 | s2cid = 211048929 }}
- {{cite journal | vauthors = Zandi Z, Kashani B, Bashash D, Poursani EM, Mousavi SA, Chahardoli B, Ghaffari SH | title = The anticancer effect of the TLR4 inhibition using TAK-242 (resatorvid) either as a single agent or in combination with chemotherapy: A novel therapeutic potential for breast cancer | journal = Journal of Cellular Biochemistry | volume = 121 | issue = 2 | pages = 1623–1634 | date = February 2020 | pmid = 31535397 | doi = 10.1002/jcb.29397 | s2cid = 202689986 }}
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