PAP-1

• CAT Number: I005241
• CAS Number: 870653-45-5
• Molecular Formula: C21H18O5
• Molecular Weight: 350.37
• Purity: ≥95%
• Synonyms: 4-(4-phenoxybutoxy)furo[3,2-g]chromen-7-one
• Target: Kv1.3
• Solubility: DMSO:9 mg/mL
• Storage: Store at -20°C
• IC50: 2 nM (EC50) [1]
• InChI: InChI=1S/C21H18O5/c22-20-9-8-16-19(26-20)14-18-17(10-13-24-18)21(16)25-12-5-4-11-23-15-6-2-1-3-7-15/h1-3,6-10,13-14H,4-5,11-12H2
• InChIKey: KINMYBBFQRSVLL-UHFFFAOYSA-N
• SMILES: O=C1C=CC2=C(OCCCCOC3=CC=CC=C3)C4=C(OC=C4)C=C2O1

PAP-1 is a selective inhibitor of Kv1.3, voltage-gated K+ channel. PAP-1 (EC50=2 nM) potently inhibits human T effector memory cell proliferation and delayed hypersensitivity.IC50 value: 2 nM (EC50) [1]in vitro: blocks Kv1.3 in a use-dependent manner, with a Hill coefficient of 2 and an EC50 of 2 nM, by preferentially binding to the C-type inactivated state of the channel. PAP-1 is 23-fold selective over Kv1.5, 33- to 125-fold selective over other Kv1-family channels, and 500- to 7500-fold selective over Kv2.1, Kv3.1, Kv3.2, Kv4.2, HERG, calcium-activated K+ channels, Na+,Ca2+, and Cl- channels [1]. The blockade of Kv1.3 results in membrane depolarization and inhibition of TEM proliferation and function. In this study, the in vitro effects of PAP-1 on T cells and the in vivo toxicity and pharmacokinetics (PK) were examined in rhesus macaques (RM) with the ultimate aim of utilizing PAP-1 to define the role of TEMs in RM infected with simian immunodeficiency virus (SIV). Electrophysiologic studies on T cells in RM revealed a Kv1.3 expression pattern similar to that in human T cells. Thus, PAP-1 effectively suppressed TEM proliferation in RM [2].in vivo: PAP-1 does not exhibit cytotoxic or phototoxic effects, is negative in the Ames test, and affects cytochrome P450-dependent enzymes only at micromolar concentrations. PAP-1 potently inhibits the proliferation of human TEM cells and suppresses delayed type hypersensitivity, a TEM cell-mediated reaction, in rats [1]. When administered intravenously, PAP-1 showed a half-life of 6.4 hrs; the volume of distribution suggested extensive distribution into extravascular compartments. When orally administered, PAP-1 was efficiently absorbed. Plasma concentrations in RM undergoing a 30-day, chronic dosing study indicated that PAP-1 levels suppressive to TEMs in vitro can be achieved and maintained in vivo at a non-toxic dose [2].

Reference

1:In silico identification of PAP-1 binding sites in the Kv1.2 potassium channel. Jorgensen C, Darré L, Vanommeslaeghe K, Omoto K, Pryde D, Domene C.Mol Pharm. 2015 Apr 6;12(4):1299-307. doi: 10.1021/acs.molpharmaceut.5b00023. Epub 2015 Mar 16. PMID: 25734225 2:Erratum to: K(+) Channels Expression in Hypertension After Arterial Injury, and Effect of Selective Kv1.3 Blockade with PAP-1 on Intimal Hyperplasia Formation. Cidad P, Novensà L, Garabito M, Batlle M, Dantas AP, Heras M, López-López JR, Pérez-García MT, Roqué M.Cardiovasc Drugs Ther. 2015 Apr;29(2):199-200. doi: 10.1007/s10557-015-6578-5. No abstract available. PMID: 25732511 3:K+ channels expression in hypertension after arterial injury, and effect of selective Kv1.3 blockade with PAP-1 on intimal hyperplasia formation. Cidad P, Novensà L, Garabito M, Batlle M, Dantas AP, Heras M, López-López JR, Pérez-García MT, Roqué M.Cardiovasc Drugs Ther. 2014 Dec;28(6):501-11. doi: 10.1007/s10557-014-6554-5. Erratum in: Cardiovasc Drugs Ther. 2015 Apr;29(2):199-200. PMID: 25348824 4:Stimulation of glucose uptake in murine soleus muscle and adipocytes by 5-(4-phenoxybutoxy)psoralen (PAP-1) may be mediated by Kv1.5 rather than Kv1.3. Ngala RA, Zaibi MS, Langlands K, Stocker CJ, Arch JR, Cawthorne MA.PeerJ. 2014 Oct 7;2:e614. doi: 10.7717/peerj.614. eCollection 2014. PMID: 25320682 Free PMC Article5:Kv1.3 in psoriatic disease: PAP-1, a small molecule inhibitor of Kv1.3 is effective in the SCID mouse psoriasis–xenograft model. Kundu-Raychaudhuri S, Chen YJ, Wulff H, Raychaudhuri SP.J Autoimmun. 2014 Dec;55:63-72. doi: 10.1016/j.jaut.2014.07.003. Epub 2014 Aug 28. PMID: 25175978 Free PMC Article6:Effect of the Kv1.3 voltage-gated potassium channel blocker PAP-1 on the initiation and progress of atherosclerosis in a rat model. Wu X, Xu R, Cao M, Ruan L, Wang X, Zhang C.Heart Vessels. 2015 Jan;30(1):108-14. doi: 10.1007/s00380-013-0462-7. Epub 2014 Jan 19. PMID: 24441938 7:Clofazimine, Psora-4 and PAP-1, inhibitors of the potassium channel Kv1.3, as a new and selective therapeutic strategy in chronic lymphocytic leukemia. Leanza L, Trentin L, Becker KA, Frezzato F, Zoratti M, Semenzato G, Gulbins E, Szabo I.Leukemia. 2013 Aug;27(8):1782-5. doi: 10.1038/leu.2013.56. Epub 2013 Feb 21. No abstract available. PMID: 23426166 8:Identification of phase-I metabolites and chronic toxicity study of the Kv1.3 blocker PAP-1 (5-(4-phenoxybutoxy)psoralen) in the rat. Hao B, Chen ZW, Zhou XJ, Zimin PI, Miljanich GP, Wulff H, Wang YX.Xenobiotica. 2011 Mar;41(3):198-211. doi: 10.3109/00498254.2010.532886. Epub 2010 Nov 11. PMID: 21070145 Free PMC Article9:99mTc-Mercaptoacetyl-Gly-Gly-Gly-PAP-1. Leung K.Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.2008 Aug 8 [updated 2008 Aug 15]. PMID: 20641925 Free Books & Documents10:Transient 5-(4-phenylbutoxy)psoralen (PAP-1) treatment dissociates developing pathologies in autoimmune optic neuritis into two distinct pathology profiles. Stokely ME, Garg P, Bhat MA, Koulen P.J Neurosci Res. 2008 Jul;86(9):2111-24. doi: 10.1002/jnr.21645. PMID: 18335521