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The synthesis and inhibitory potencies against botulinum neurotoxin serotype A light chain (BoNT/A LC) using in vitro HPLC based enzymatic assay for various steroidal, benzothiophene, thiophene, and adamantane 4-aminoquinoline derivatives are described. In addition, the compounds were evaluated for the activity against BoNT/A holotoxin in mouse embryonic stem cell derived motor neurons. Steroidal derivative 16 showed remarkable protection (up to 89% of uncleaved SNAP-25) even when administered 30 min postintoxication. This appears to be the first example of LC inhibitors antagonizing BoNT intoxication in mouse embryonic stem cell derived motor neurons (mES-MNs) in a postexposure model. Oral administration of 16 was well tolerated in the mouse up to 600 mg/kg, q.d. Although adequate unbound drug levels were not achieved at this dose, the favorable in vitro ADMET results strongly support further work in this series.

Titel:	New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model.
Autor/in / Beteiligte Person:	Konstantinović, J ; Kiris, E ; Kota, KP ; Kugelman-Tonos, J ; Videnović, M ; Cazares, LH ; Terzić Jovanović, N ; Verbić, TŽ ; Andjelković, B ; Duplantier, AJ ; Bavari, S ; Šolaja, BA
Zeitschrift:	Journal of medicinal chemistry, Jg. 61 (2018-02-22), Heft 4, S. 1595-1608
Veröffentlichung:	Washington Dc : American Chemical Society ; <i>Original Publication</i>: [Easton, Pa.] : American Chemical Society, [c1963-, 2018
Medientyp:	academicJournal
ISSN:	1520-4804 (electronic)
DOI:	10.1021/acs.jmedchem.7b01710
Schlagwort:	Adamantane analogs & derivatives Aminoquinolines chemistry Animals Mice Molecular Docking Simulation Motor Neurons drug effects Mouse Embryonic Stem Cells cytology Steroids chemistry Synaptosomal-Associated Protein 25 metabolism Thiophenes chemistry Toxicity Tests Aminoquinolines pharmacology Botulinum Toxins, Type A antagonists & inhibitors Motor Neurons pathology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [J Med Chem] 2018 Feb 22; Vol. 61 (4), pp. 1595-1608. <i>Date of Electronic Publication: </i>2018 Feb 06. MeSH Terms: Aminoquinolines / pharmacology ; Botulinum Toxins, Type A / antagonists & inhibitors ; Motor Neurons / *pathology ; Adamantane / analogs & derivatives ; Aminoquinolines / chemistry ; Animals ; Mice ; Molecular Docking Simulation ; Motor Neurons / drug effects ; Mouse Embryonic Stem Cells / cytology ; Steroids / chemistry ; Synaptosomal-Associated Protein 25 / metabolism ; Thiophenes / chemistry ; Toxicity Tests References: Neuropharmacology. 2010 Jun;58(8):1189-98. (PMID: 20211192) ; Nat Rev Drug Discov. 2010 Dec;9(12 ):929-39. (PMID: 21119731) ; J Pharm Biomed Anal. 1996 Aug;14(11):1405-13. (PMID: 8877846) ; J Infect Dis. 2014 Jan 15;209(2):183-91. (PMID: 24106296) ; Org Lett. 2006 Apr 13;8(8):1729-32. (PMID: 16597152) ; Cell. 2002 Aug 9;110(3):385-97. (PMID: 12176325) ; J Biomol Screen. 2007 Apr;12(3):370-7. (PMID: 17332092) ; Eur J Med Chem. 2012 Jul;53:374-9. (PMID: 22516424) ; Molecules. 2017 Feb 24;22(3):. (PMID: 28245583) ; J Biol Chem. 2008 Sep 19;283(38):25944-51. (PMID: 18658150) ; Sci Rep. 2015 Dec 16;5:17513. (PMID: 26670952) ; Chem Commun (Camb). 2015 Apr 11;51(28):6226-9. (PMID: 25759983) ; PLoS One. 2010 Apr 13;5(4):e10129. (PMID: 20405003) ; Curr Opin Chem Biol. 2003 Jun;7(3):402-8. (PMID: 12826129) ; J Biomol Screen. 2010 Sep;15(8):928-36. (PMID: 20720092) ; Toxicon. 2012 Nov;60(6):1180-90. (PMID: 22960451) ; Expert Opin Drug Discov. 2017 May;12 (5):497-510. (PMID: 28271909) ; Neurotox Res. 2015 May;27(4):384-98. (PMID: 25782580) ; J Med Chem. 2007 May 3;50(9):2127-36. (PMID: 17417831) ; Biochim Biophys Acta. 2013 Dec;1830(12):5435-43. (PMID: 23665585) ; Cell Rep. 2014 Sep 25;8(6):1870-1878. (PMID: 25220457) ; J Sep Sci. 2014 Nov;37(21):3074-81. (PMID: 25146246) ; FEBS Lett. 1999 Jul 30;456(1):137-42. (PMID: 10452545) ; Toxicon. 2017 Oct;137:36-47. (PMID: 28698055) ; PLoS One. 2015 Jun 10;10 (6):e0129264. (PMID: 26061731) ; Bioorg Med Chem. 2006 Aug 15;14(16):5605-15. (PMID: 16690319) ; J Med Chem. 2017 Jan 12;60(1):338-348. (PMID: 27966961) ; FEBS Lett. 2007 Oct 16;581(25):4803-8. (PMID: 17889852) ; ACS Chem Biol. 2017 May 19;12 (5):1425-1434. (PMID: 28350449) ; Curr Top Microbiol Immunol. 2013;364:257-85. (PMID: 23239357) ; J Am Chem Soc. 2016 May 4;138(17 ):5568-75. (PMID: 27070533) ; Bioorg Med Chem. 2004 Mar 1;12(5):1177-82. (PMID: 14980628) ; Spectrochim Acta A Mol Biomol Spectrosc. 2018 Mar 5;192:128-139. (PMID: 29128746) ; Curr Opin Pharmacol. 2005 Jun;5(3):274-9. (PMID: 15907915) ; Toxins (Basel). 2011 Mar;3(3):207-17. (PMID: 22069707) ; Biochem Biophys Res Commun. 2003 Oct 10;310(1):84-93. (PMID: 14511652) ; J Med Chem. 2014 May 22;57(10):4134-53. (PMID: 24742203) ; Drug Metab Rev. 2001 May;33(2):161-235. (PMID: 11495502) ; J Med Chem. 2016 Jan 14;59(1):264-81. (PMID: 26640981) ; Nat Rev Microbiol. 2014 Aug;12(8):535-49. (PMID: 24975322) ; J Am Chem Soc. 1946 Sep;68(9):1807-9. (PMID: 21001098) ; Expert Rev Mol Diagn. 2014 Mar;14(2):153-68. (PMID: 24450833) ; Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2602-7. (PMID: 17293454) ; J Med Chem. 2008 Aug 14;51(15):4388-91. (PMID: 18637666) ; J Am Chem Soc. 2017 May 31;139(21):7264-7272. (PMID: 28475321) ; Curr Top Med Chem. 2016;16(21):2330-49. (PMID: 27072693) ; Stem Cell Res. 2011 May;6(3):195-205. (PMID: 21353660) Grant Information: R33 AI101387 United States AI NIAID NIH HHS; U01 AI082051 United States AI NIAID NIH HHS Substance Nomenclature: 0 (Aminoquinolines) ; 0 (SNAP25 protein, human) ; 0 (Steroids) ; 0 (Synaptosomal-Associated Protein 25) ; 0 (Thiophenes) ; 073790YQ2G (benzothiophene) ; EC 3.4.24.69 (Botulinum Toxins, Type A) ; GTE5P5L97N (4-aminoquinoline) ; PJY633525U (Adamantane) Entry Date(s): Date Created: 20180201 Date Completed: 20190415 Latest Revision: 20190415 Update Code: 20240513 PubMed Central ID: PMC5833296

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New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model.