Israpafant Explained

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]

See also

Notes and References

  1. Hirota N, Yasuda D, Hashidate T, Yamamoto T, Yamaguchi S, Nagamune T, Nagase T, Shimizu T, Nakamura M . 6 . Amino acid residues critical for endoplasmic reticulum export and trafficking of platelet-activating factor receptor . The Journal of Biological Chemistry . 285 . 8 . 5931–40 . February 2010 . 20007715 . 2820818 . 10.1074/jbc.M109.066282 . free .
  2. Hozawa S, Haruta Y, Ishioka S, Yamakido M . 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 . October 1995 . 7551370 . 10.1164/ajrccm.152.4.7551370 .
  3. Takehara S, Mikashima H, Muramoto Y, Terasawa M, Setoguchi M, Tahara T . 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 . December 1990 . 1965554 . 10.1016/0090-6980(90)90002-D .
  4. Komatsu H, Amano M, Yamaguchi S, Sugahara K . Inhibition of activation of human peripheral blood eosinophils by Y-24180, an antagonist to platelet-activating factor receptor . Life Sciences . 65 . 13 . PL171-6 . 10503965 . 10.1016/s0024-3205(99)00385-9 . 1999 .
  5. Mizuki M, Komatsu H, Akiyama Y, Iwane S, Tsuda T . 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 . 1999 . 10579457 . 10.1016/s0024-3205(99)00470-1 .
  6. Satoh T, Tahara E, Yamada T, Watanabe C, Itoh T, Terasawa K, Nagai H, Saiki I . 6 . Differential effect of antiallergic drugs on IgE-mediated cutaneous reaction in passively sensitized mice . Pharmacology . 60 . 2 . 97–104 . February 2000 . 10657759 . 10.1159/000028353 . 6264992 .
  7. Kawaguchi A, Sugimoto K, Fujimura A . Preventive effect of platelet-activating factor antagonist, Y-24180, against cyclosporine-induced acute nephrotoxicity . Life Sciences . 68 . 10 . 1181–90 . January 2001 . 11228102 . 10.1016/s0024-3205(00)01028-6 .
  8. Chao YY, Jan CR . Effect of Y-24180 on Ca2+ movement and proliferation in renal tubular cells . Life Sciences . 74 . 7 . 923–33 . January 2004 . 14659980 . 10.1016/j.lfs.2003.09.033 .

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