Israpafant

Israpafant (Y-24180) is a drug which acts as a selective antagonist for the platelet-activating factor receptor,[1] and was originally developed for the treatment of asthma.[2] 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.[3] Israpafant has been found to inhibit the activation of eosinophil cells,[4][5][6] and consequently delays the development of immune responses. It has also been shown to have anti-nephrotoxic properties,[7] and to mobilize calcium transport.[8]

Israpafant
Legal status
Legal status
Identifiers
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
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC28H29ClN4S
Molar mass489.08 g·mol−1
3D model (JSmol)
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
InChI
  • InChI=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
  • Key:RMSWMRJVUJSDGN-GOSISDBHSA-N

See also

References
  1. Hirota N, Yasuda D, Hashidate T, Yamamoto T, Yamaguchi S, Nagamune T, et al. (February 2010). "Amino acid residues critical for endoplasmic reticulum export and trafficking of platelet-activating factor receptor". The Journal of Biological Chemistry. 285 (8): 5931–40. doi:10.1074/jbc.M109.066282. PMC 2820818. PMID 20007715.
  2. Hozawa S, Haruta Y, Ishioka S, Yamakido M (October 1995). "Effects of a PAF antagonist, Y-24180, on bronchial hyperresponsiveness in patients with asthma". American Journal of Respiratory and Critical Care Medicine. 152 (4 Pt 1): 1198–202. doi:10.1164/ajrccm.152.4.7551370. PMID 7551370.
  3. Takehara S, Mikashima H, Muramoto Y, Terasawa M, Setoguchi M, Tahara T (December 1990). "Pharmacological actions of Y-24180, a new specific antagonist of platelet activating factor (PAF): II. Interactions with PAF and benzodiazepine receptors". Prostaglandins. 40 (6): 571–83. doi:10.1016/0090-6980(90)90002-D. PMID 1965554.
  4. Komatsu H, Amano M, Yamaguchi S, Sugahara K (1999). "Inhibition of activation of human peripheral blood eosinophils by Y-24180, an antagonist to platelet-activating factor receptor". Life Sciences. 65 (13): PL171-6. doi:10.1016/s0024-3205(99)00385-9. PMID 10503965.
  5. Mizuki M, Komatsu H, Akiyama Y, Iwane S, Tsuda T (1999). "Inhibition of eosinophil activation in bronchoalveolar lavage fluid from atopic asthmatics by Y-24180, an antagonist to platelet-activating factor". Life Sciences. 65 (20): 2031–9. doi:10.1016/s0024-3205(99)00470-1. PMID 10579457.
  6. Satoh T, Tahara E, Yamada T, Watanabe C, Itoh T, Terasawa K, et al. (February 2000). "Differential effect of antiallergic drugs on IgE-mediated cutaneous reaction in passively sensitized mice". Pharmacology. 60 (2): 97–104. doi:10.1159/000028353. PMID 10657759. S2CID 6264992.
  7. Kawaguchi A, Sugimoto K, Fujimura A (January 2001). "Preventive effect of platelet-activating factor antagonist, Y-24180, against cyclosporine-induced acute nephrotoxicity". Life Sciences. 68 (10): 1181–90. doi:10.1016/s0024-3205(00)01028-6. PMID 11228102.
  8. Chao YY, Jan CR (January 2004). "Effect of Y-24180 on Ca2+ movement and proliferation in renal tubular cells". Life Sciences. 74 (7): 923–33. doi:10.1016/j.lfs.2003.09.033. PMID 14659980.
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