israpafant
{{Short description|Chemical compound}}
{{Drugbox
| IUPAC_name = (6R)-4-(2-Chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine
| image = Israpafant.svg
| width = 265
| tradename =
| legal_US = Investigational New Drug
| legal_status =
| bioavailability =
| metabolism =
| elimination_half-life =
| excretion =
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 117279-73-9
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = O3MCV749SW
| PubChem = 636426
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| ChemSpiderID = 552203
| C=28 | H=29 | Cl=1 | N=4 | S=1
| smiles = C[C@@H]1C2=NN=C(N2C3=C(C=C(S3)CCC4=CC=C(C=C4)CC(C)C)C(=N1)C5=CC=CC=C5Cl)C
| StdInChI = 1S/C28H29ClN4S/c1-17(2)15-21-11-9-20(10-12-21)13-14-22-16-24-26(23-7-5-6-8-25(23)29)30-18(3)27-32-31-19(4)33(27)28(24)34-22/h5-12,16-18H,13-15H2,1-4H3/t18-/m1/s1
| StdInChIKey = RMSWMRJVUJSDGN-GOSISDBHSA-N
}}
Israpafant (Y-24180) is a drug which acts as a selective antagonist for the platelet-activating factor receptor,{{cite journal | vauthors = Hirota N, Yasuda D, Hashidate T, Yamamoto T, Yamaguchi S, Nagamune T, Nagase T, Shimizu T, Nakamura M | display-authors = 6 | title = Amino acid residues critical for endoplasmic reticulum export and trafficking of platelet-activating factor receptor | journal = The Journal of Biological Chemistry | volume = 285 | issue = 8 | pages = 5931–40 | date = February 2010 | pmid = 20007715 | pmc = 2820818 | doi = 10.1074/jbc.M109.066282 | doi-access = free }} and was originally developed for the treatment of asthma.{{cite journal | vauthors = Hozawa S, Haruta Y, Ishioka S, Yamakido M | title = Effects of a PAF antagonist, Y-24180, on bronchial hyperresponsiveness in patients with asthma | journal = American Journal of Respiratory and Critical Care Medicine | volume = 152 | issue = 4 Pt 1 | pages = 1198–202 | date = October 1995 | pmid = 7551370 | doi = 10.1164/ajrccm.152.4.7551370 }} Its chemical structure is a thienotriazolodiazepine, closely related to the sedative benzodiazepine derivative etizolam. However israpafant binds far more tightly to the platelet-activating factor receptor, with an IC50 of 0.84nM for inhibiting PAF-induced human platelet aggregation (compared to etizolam's IC50 of 998nM at this target), while it binds only weakly to benzodiazepine receptors, with a Ki of 3680nM.{{cite journal | vauthors = Takehara S, Mikashima H, Muramoto Y, Terasawa M, Setoguchi M, Tahara T | title = Pharmacological actions of Y-24180, a new specific antagonist of platelet activating factor (PAF): II. Interactions with PAF and benzodiazepine receptors | journal = Prostaglandins | volume = 40 | issue = 6 | pages = 571–83 | date = December 1990 | pmid = 1965554 | doi = 10.1016/0090-6980(90)90002-D }} Israpafant has been found to inhibit the activation of eosinophil cells,{{cite journal | vauthors = Komatsu H, Amano M, Yamaguchi S, Sugahara K | title = Inhibition of activation of human peripheral blood eosinophils by Y-24180, an antagonist to platelet-activating factor receptor | journal = Life Sciences | volume = 65 | issue = 13 | pages = PL171-6 | pmid = 10503965 | doi = 10.1016/s0024-3205(99)00385-9 | year = 1999 }}{{cite journal | vauthors = Mizuki M, Komatsu H, Akiyama Y, Iwane S, Tsuda T | title = Inhibition of eosinophil activation in bronchoalveolar lavage fluid from atopic asthmatics by Y-24180, an antagonist to platelet-activating factor | journal = Life Sciences | volume = 65 | issue = 20 | pages = 2031–9 | year = 1999 | pmid = 10579457 | doi = 10.1016/s0024-3205(99)00470-1 }}{{cite journal | vauthors = Satoh T, Tahara E, Yamada T, Watanabe C, Itoh T, Terasawa K, Nagai H, Saiki I | display-authors = 6 | title = Differential effect of antiallergic drugs on IgE-mediated cutaneous reaction in passively sensitized mice | journal = Pharmacology | volume = 60 | issue = 2 | pages = 97–104 | date = February 2000 | pmid = 10657759 | doi = 10.1159/000028353 | s2cid = 6264992 }} and consequently delays the development of immune responses. It has also been shown to have anti-nephrotoxic properties,{{cite journal | vauthors = Kawaguchi A, Sugimoto K, Fujimura A | title = Preventive effect of platelet-activating factor antagonist, Y-24180, against cyclosporine-induced acute nephrotoxicity | journal = Life Sciences | volume = 68 | issue = 10 | pages = 1181–90 | date = January 2001 | pmid = 11228102 | doi = 10.1016/s0024-3205(00)01028-6 }} and to mobilize calcium transport.{{cite journal | vauthors = Chao YY, Jan CR | title = Effect of Y-24180 on Ca2+ movement and proliferation in renal tubular cells | journal = Life Sciences | volume = 74 | issue = 7 | pages = 923–33 | date = January 2004 | pmid = 14659980 | doi = 10.1016/j.lfs.2003.09.033 }}