Israpafant

Israpafant
Legal status

Legal status	Investigational New Drug
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	117279-73-9^Y
PubChem (CID)	636426
ChemSpider	552203
Chemical and physical data
Formula	C₂₈H₂₉ClN₄S
Molar mass	489.074 g/mol
3D model (Jmol)	Interactive image
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

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]

References

↑ Hirota N, Yasuda D, Hashidate T, Yamamoto T, Yamaguchi S, Nagamune T, Nagase T, Shimizu T, Nakamura M. Amino acid residues critical for endoplasmic reticulum export and trafficking of platelet-activating factor receptor. Journal of Biological Chemistry. 2010 Feb 19;285(8):5931-40. doi: 10.1074/jbc.M109.066282. PMID 20007715
↑ Hozawa, S (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): 1198–1202. doi:10.1164/ajrccm.152.4.7551370.
↑ Takehara, S. (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): 571–583. doi:10.1016/0090-6980(90)90002-D.
↑ 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. 1999;65(13):PL171-6. PMID 10503965
↑ 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. 1999;65(20):2031-9. PMID 10579457
↑ Satoh T, Tahara E, Yamada T, Watanabe C, Itoh T, Terasawa K, Nagai H, Saiki I. Differential effect of antiallergic drugs on IgE-mediated cutaneous reaction in passively sensitized mice. Pharmacology. 2000 Feb;60(2):97-104. PMID 10657759
↑ Kawaguchi A, Sugimoto K, Fujimura A. Preventive effect of platelet-activating factor antagonist, Y-24180, against cyclosporine-induced acute nephrotoxicity. Life Sciences. 2001 Jan 26;68(10):1181-90. PMID 11228102
↑ Chao YY, Jan CR. Effect of Y-24180 on Ca2+ movement and proliferation in renal tubular cells. Life Sciences. 2004 Jan 2;74(7):923-33. PMID 14659980

PAF signaling modulators

PAF

Agonists	C-PAF Edelfosine PAF

Antagonists	A-85783 ABT-491 Apafant BN-50739 BN-52063 Cetirizine CV-3988 CV-6209 Etizolam Ginkgolide B (BN-52021) Israpafant Kadsurenone L-652 Lexipafant Loratadine PCA-4248 Rupatadine SM-12502 SR-27417 SRI 63-441 Terfenadine WEB-2086 Yangambin

Others

Precursors	Choline ATP Phosphocholine PC LPC AAG

Benzodiazepines

1,4-Benzodiazepines	2-Oxoquazepam 3-Hydroxyphenazepam Bromazepam Camazepam Carburazepam Chlordiazepoxide Cinazepam Cinolazepam Clonazepam Clorazepate Cyprazepam Delorazepam Demoxepam Desmethylflunitrazepam Devazepide* Diazepam Diclazepam Doxefazepam Elfazepam Ethyl carfluzepate Ethyl dirazepate Ethyl loflazepate Flubromazepam Fletazepam Fludiazepam Flunitrazepam Flurazepam Flutemazepam Flutoprazepam Fosazepam Gidazepam Halazepam Iclazepam Irazepine Kenazepine Ketazolam Lorazepam Lormetazepam Lufuradom* Meclonazepam Medazepam Menitrazepam Metaclazepam Motrazepam N-Desalkylflurazepam Nifoxipam Nimetazepam Nitrazepam Nitrazepate Nordazepam Nortetrazepam Oxazepam Phenazepam Pinazepam Pivoxazepam Prazepam Proflazepam Quazepam QH-II-66 Reclazepam RO4491533* Ro5-4864* Sulazepam Temazepam Tetrazepam Tifluadom* Tolufazepam Triflunordazepam Tuclazepam Uldazepam

1,5-Benzodiazepines	Arfendazam Clobazam CP-1414S Lofendazam Triflubazam

2,3-Benzodiazepines*	Girisopam GYKI-52466 GYKI-52895 Nerisopam Talampanel Tofisopam

Triazolobenzodiazepines	Adinazolam Alprazolam Clonazolam Estazolam Flubromazolam Nitrazolam Pyrazolam Triazolam

Imidazobenzodiazepines	Bretazenil Climazolam EVT-201 FG-8205 Flumazenil Imidazenil ¹²³I-Iomazenil L-655,708 Loprazolam Midazolam PWZ-029 Remimazolam Ro15-4513 Ro48-6791 Ro48-8684 Ro4938581 Sarmazenil SH-053-R-CH3-2′F

Oxazolobenzodiazepines	Cloxazolam Flutazolam Haloxazolam Mexazolam Oxazolam

Thienodiazepines	Bentazepam Clotiazepam

Thienotriazolodiazepines	Brotizolam Ciclotizolam Deschloroetizolam Etizolam Israpafant* JQ1* Metizolam

Thienobenzodiazepines*	Olanzapine Telenzepine

Pyridodiazepines	Lopirazepam

Pyridotriazolodiazepines	Zapizolam

Pyrazolodiazepines	Razobazam* Ripazepam Zolazepam Zomebazam Zometapine*

Pyrrolodiazepines	Premazepam

Tetrahydroisoquinobenzodiazepines	Clazolam

Pyrrolobenzodiazepines*	Anthramycin

Benzodiazepine prodrugs	Avizafone Rilmazafone

* atypical activity profile (not GABA_A receptor ligands)

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Israpafant

See also

References