Academic Journal
View in EDS

Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome.

Bibliographic Details
Title: Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome.
Authors: Borgogno M; Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy., Savardi A; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.; Dulbecco Telethon Institute, 38123 Rome, Italy., Manigrasso J; Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy., Turci A; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.; Università degli Studi di Genova, via Balbi, 5, 16126 Genoa, Italy., Portioli C; Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy., Ottonello G; Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy., Bertozzi SM; Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy., Armirotti A; Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy., Contestabile A; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy., Cancedda L; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.; Dulbecco Telethon Institute, 38123 Rome, Italy., De Vivo M; Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.
Source: Journal of medicinal chemistry [J Med Chem] 2021 Jul 22; Vol. 64 (14), pp. 10203-10229. Date of Electronic Publication: 2021 Jun 17.
Publication Type: Journal Article; Research Support, Non-U.S. Gov't
Language: English
Journal Info: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
Imprint Name(s): Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
MeSH Terms: Drug Design*, Down Syndrome/*drug therapy , Solute Carrier Family 12, Member 2/*metabolism, Animals ; Cells, Cultured ; Dose-Response Relationship, Drug ; Down Syndrome/metabolism ; Female ; HEK293 Cells ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Molecular Structure ; Structure-Activity Relationship
Abstract: Intracellular chloride concentration [Cl - ] i is defective in several neurological disorders. In neurons, [Cl - ] i is mainly regulated by the action of the Na + -K + -Cl - importer NKCC1 and the K + -Cl - exporter KCC2. Recently, we have reported the discovery of ARN23746 as the lead candidate of a novel class of selective inhibitors of NKCC1. Importantly, ARN23746 is able to rescue core symptoms of Down syndrome (DS) and autism in mouse models. Here, we describe the discovery and extensive characterization of this chemical class of selective NKCC1 inhibitors, with focus on ARN23746 and other promising derivatives. In particular, we present compound 40 ( ARN24092 ) as a backup/follow-up lead with in vivo efficacy in a mouse model of DS. These results further strengthen the potential of this new class of compounds for the treatment of core symptoms of brain disorders characterized by the defective NKCC1/KCC2 expression ratio.
References: Neuropharmacology. 2020 Jan 1;162:107754. (PMID: 31476353)
J Med Chem. 2019 Mar 28;62(6):2851-2893. (PMID: 30295477)
J Child Neurol. 2009 May;24(5):572-6. (PMID: 19406757)
J Comput Aided Mol Des. 2006 Oct-Nov;20(10-11):647-71. (PMID: 17124629)
Adv Chronic Kidney Dis. 2017 Mar;24(2):72-79. (PMID: 28284382)
J Neurosci. 2012 Jul 4;32(27):9217-27. (PMID: 22764230)
Br J Clin Pharmacol. 2017 Jun;83(6):1341-1349. (PMID: 28002877)
Neurosci Biobehav Rev. 2018 Jul;90:260-271. (PMID: 29729285)
Ann Neurol. 2014 Apr;75(4):550-62. (PMID: 24615913)
Front Neurol. 2017 Sep 08;8:469. (PMID: 28943860)
Nat Genet. 1995 Oct;11(2):177-84. (PMID: 7550346)
Science. 2019 Oct 25;366(6464):505-508. (PMID: 31649201)
Nature. 2019 Aug;572(7770):488-492. (PMID: 31367042)
Front Neurosci. 2019 Apr 24;13:310. (PMID: 31068771)
Nat Protoc. 2006;1(5):2406-15. (PMID: 17406484)
Clin Neuropharmacol. 2016 Jan-Feb;39(1):57-9. (PMID: 26757306)
Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2046-2049. (PMID: 28893923)
Transl Psychiatry. 2012 Dec 11;2:e202. (PMID: 23233021)
Front Cell Neurosci. 2017 Mar 07;11:54. (PMID: 28326014)
Neuropharmacology. 2018 Dec;143:186-204. (PMID: 30248303)
Chem. 2020 Aug 06;6(8):2073-2096. (PMID: 32818158)
Sci Rep. 2018 Feb 26;8(1):3602. (PMID: 29483603)
Transl Psychiatry. 2020 Jan 27;10(1):9. (PMID: 32066666)
Acta Paediatr. 2010 Dec;99(12):1885-8. (PMID: 20608900)
Trends Neurosci. 2017 Sep;40(9):536-554. (PMID: 28818303)
Schizophr Res. 2017 Jun;184:145-146. (PMID: 27956008)
Epilepsia. 2013 Jan;54(1):e9-12. (PMID: 23061490)
Acta Paediatr. 2013 Jun;102(6):e288-90. (PMID: 23647528)
J Am Acad Child Adolesc Psychiatry. 2021 Jul;60(7):865-876. (PMID: 32730977)
Epilepsy Behav. 2016 Jun;59:42-9. (PMID: 27088517)
Commun Biol. 2021 Feb 17;4(1):226. (PMID: 33597714)
J Med Chem. 2013 Jan 10;56(1):2-12. (PMID: 23075026)
Acta Paediatr. 2021 May;110(5):1548-1553. (PMID: 33336381)
Transl Psychiatry. 2017 Mar 14;7(3):e1056. (PMID: 28291262)
Cell Res. 2021 Apr;31(4):482-484. (PMID: 33199848)
Ann Neurol. 2021 Feb;89(2):327-340. (PMID: 33201535)
Medicine (Baltimore). 2020 Jan;99(2):e18661. (PMID: 31914053)
Mamm Genome. 2011 Dec;22(11-12):685-91. (PMID: 21953412)
Clin Neuropharmacol. 2016 Mar-Apr;39(2):115-7. (PMID: 26966887)
J Otol. 2016 Dec;11(4):145-156. (PMID: 29937824)
Chem Biol Drug Des. 2006 May;67(5):370-2. (PMID: 16784462)
J Child Adolesc Psychopharmacol. 2015 Sep;25(7):585-8. (PMID: 26258842)
PLoS One. 2012;7(4):e35373. (PMID: 22506078)
Front Cell Neurosci. 2014 May 22;8:119. (PMID: 24904277)
Ren Fail. 2014 Aug;36(7):1051-5. (PMID: 24940940)
J Clin Neurosci. 2020 Nov;81:477-484. (PMID: 33222966)
Mol Autism. 2020 May 7;11(1):30. (PMID: 32381101)
Autism. 2015 Feb;19(2):149-57. (PMID: 24343334)
Nat Commun. 2020 Feb 21;11(1):1016. (PMID: 32081947)
Elife. 2020 Apr 14;9:. (PMID: 32286222)
Tunis Med. 2019 Aug - Sep;97(8-9):971-977. (PMID: 32173844)
CNS Drugs. 2019 Mar;33(3):283-291. (PMID: 30784026)
BMJ Case Rep. 2014 Jan 31;2014:. (PMID: 24488662)
J Neurosci. 2007 May 9;27(19):5224-35. (PMID: 17494709)
Nat Med. 2015 Apr;21(4):318-26. (PMID: 25774849)
Pediatrics. 2015 Aug;136(2):e539-43. (PMID: 26216321)
Structure. 2020 Sep 1;28(9):1051-1060.e4. (PMID: 32679039)
Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5383-8. (PMID: 19279215)
Substance Nomenclature: 0 (SLC12A2 protein, human)
0 (Solute Carrier Family 12, Member 2)
Entry Date(s): Date Created: 20210617 Date Completed: 20211006 Latest Revision: 20211006
Update Code: 20221216
PubMed Central ID: PMC8311653
DOI: 10.1021/acs.jmedchem.1c00603
PMID: 34137257
Database: MEDLINE
ResultId 1
Header cmedm
MEDLINE
34137257
3
Academic Journal
academicJournal
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&scope=site&db=cmedm&AN=34137257
FullText Array ( [Availability] => 0 )
Items Array ( [Name] => Title [Label] => Title [Group] => Ti [Data] => Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome. )
Array ( [Name] => Author [Label] => Authors [Group] => Au [Data] => <searchLink fieldCode="AU" term="%22Borgogno+M%22">Borgogno M</searchLink>; Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.<br /><searchLink fieldCode="AU" term="%22Savardi+A%22">Savardi A</searchLink>; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.; Dulbecco Telethon Institute, 38123 Rome, Italy.<br /><searchLink fieldCode="AU" term="%22Manigrasso+J%22">Manigrasso J</searchLink>; Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.<br /><searchLink fieldCode="AU" term="%22Turci+A%22">Turci A</searchLink>; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.; Università degli Studi di Genova, via Balbi, 5, 16126 Genoa, Italy.<br /><searchLink fieldCode="AU" term="%22Portioli+C%22">Portioli C</searchLink>; Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.<br /><searchLink fieldCode="AU" term="%22Ottonello+G%22">Ottonello G</searchLink>; Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.<br /><searchLink fieldCode="AU" term="%22Bertozzi+SM%22">Bertozzi SM</searchLink>; Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.<br /><searchLink fieldCode="AU" term="%22Armirotti+A%22">Armirotti A</searchLink>; Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.<br /><searchLink fieldCode="AU" term="%22Contestabile+A%22">Contestabile A</searchLink>; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.<br /><searchLink fieldCode="AU" term="%22Cancedda+L%22">Cancedda L</searchLink>; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.; Dulbecco Telethon Institute, 38123 Rome, Italy.<br /><searchLink fieldCode="AU" term="%22De+Vivo+M%22">De Vivo M</searchLink>; Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy. )
Array ( [Name] => TitleSource [Label] => Source [Group] => Src [Data] => <searchLink fieldCode="JN" term="%229716531%22">Journal of medicinal chemistry</searchLink> [J Med Chem] 2021 Jul 22; Vol. 64 (14), pp. 10203-10229. <i>Date of Electronic Publication: </i>2021 Jun 17. )
Array ( [Name] => TypePub [Label] => Publication Type [Group] => TypPub [Data] => Journal Article; Research Support, Non-U.S. Gov't )
Array ( [Name] => Language [Label] => Language [Group] => Lang [Data] => English )
Array ( [Name] => TitleSource [Label] => Journal Info [Group] => Src [Data] => <i>Publisher: </i><searchLink fieldCode="PB" term="%22American+Chemical+Society%22">American Chemical Society </searchLink><i>Country of Publication: </i>United States <i>NLM ID: </i>9716531 <i>Publication Model: </i>Print-Electronic <i>Cited Medium: </i>Internet <i>ISSN: </i>1520-4804 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2200222623%22">00222623 </searchLink><i>NLM ISO Abbreviation: </i>J Med Chem <i>Subsets: </i>MEDLINE )
Array ( [Name] => PublisherInfo [Label] => Imprint Name(s) [Group] => PubInfo [Data] => <i>Publication</i>: Washington Dc : American Chemical Society<br /><i>Original Publication</i>: [Easton, Pa.] : American Chemical Society, [c1963- )
Array ( [Name] => SubjectMESH [Label] => MeSH Terms [Group] => Su [Data] => <searchLink fieldCode="MM" term="%22Drug+Design%22">Drug Design*</searchLink><br /><searchLink fieldCode="MM" term="%22Down+Syndrome%22">Down Syndrome</searchLink>/<searchLink fieldCode="MM" term="%22Down+Syndrome+drug+therapy%22">*drug therapy</searchLink> <br /><searchLink fieldCode="MM" term="%22Solute+Carrier+Family+12%2C+Member+2%22">Solute Carrier Family 12, Member 2</searchLink>/<searchLink fieldCode="MM" term="%22Solute+Carrier+Family+12%2C+Member+2+metabolism%22">*metabolism</searchLink><br /><searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Cells%2C+Cultured%22">Cells, Cultured</searchLink> ; <searchLink fieldCode="MH" term="%22Dose-Response+Relationship%2C+Drug%22">Dose-Response Relationship, Drug</searchLink> ; <searchLink fieldCode="MH" term="%22Down+Syndrome%22">Down Syndrome</searchLink>/<searchLink fieldCode="MH" term="%22Down+Syndrome+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Female%22">Female</searchLink> ; <searchLink fieldCode="MH" term="%22HEK293+Cells%22">HEK293 Cells</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Male%22">Male</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%22">Mice</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%2C+Inbred+C57BL%22">Mice, Inbred C57BL</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%2C+Transgenic%22">Mice, Transgenic</searchLink> ; <searchLink fieldCode="MH" term="%22Molecular+Structure%22">Molecular Structure</searchLink> ; <searchLink fieldCode="MH" term="%22Structure-Activity+Relationship%22">Structure-Activity Relationship</searchLink> )
Array ( [Name] => Abstract [Label] => Abstract [Group] => Ab [Data] => Intracellular chloride concentration [Cl <superscript>-</superscript> ] <subscript>i</subscript> is defective in several neurological disorders. In neurons, [Cl <superscript>-</superscript> ] <subscript>i</subscript> is mainly regulated by the action of the Na <superscript>+</superscript> -K <superscript>+</superscript> -Cl <superscript>-</superscript> importer NKCC1 and the K <superscript>+</superscript> -Cl <superscript>-</superscript> exporter KCC2. Recently, we have reported the discovery of ARN23746 as the lead candidate of a novel class of selective inhibitors of NKCC1. Importantly, ARN23746 is able to rescue core symptoms of Down syndrome (DS) and autism in mouse models. Here, we describe the discovery and extensive characterization of this chemical class of selective NKCC1 inhibitors, with focus on ARN23746 and other promising derivatives. In particular, we present compound 40 ( ARN24092 ) as a backup/follow-up lead with in vivo efficacy in a mouse model of DS. These results further strengthen the potential of this new class of compounds for the treatment of core symptoms of brain disorders characterized by the defective NKCC1/KCC2 expression ratio. )
Array ( [Name] => Ref [Label] => References [Group] => RefInfo [Data] => Neuropharmacology. 2020 Jan 1;162:107754. (PMID: <searchLink fieldCode="PM" term="%2231476353%22">31476353)</searchLink><br />J Med Chem. 2019 Mar 28;62(6):2851-2893. (PMID: <searchLink fieldCode="PM" term="%2230295477%22">30295477)</searchLink><br />J Child Neurol. 2009 May;24(5):572-6. (PMID: <searchLink fieldCode="PM" term="%2219406757%22">19406757)</searchLink><br />J Comput Aided Mol Des. 2006 Oct-Nov;20(10-11):647-71. (PMID: <searchLink fieldCode="PM" term="%2217124629%22">17124629)</searchLink><br />Adv Chronic Kidney Dis. 2017 Mar;24(2):72-79. (PMID: <searchLink fieldCode="PM" term="%2228284382%22">28284382)</searchLink><br />J Neurosci. 2012 Jul 4;32(27):9217-27. (PMID: <searchLink fieldCode="PM" term="%2222764230%22">22764230)</searchLink><br />Br J Clin Pharmacol. 2017 Jun;83(6):1341-1349. (PMID: <searchLink fieldCode="PM" term="%2228002877%22">28002877)</searchLink><br />Neurosci Biobehav Rev. 2018 Jul;90:260-271. (PMID: <searchLink fieldCode="PM" term="%2229729285%22">29729285)</searchLink><br />Ann Neurol. 2014 Apr;75(4):550-62. (PMID: <searchLink fieldCode="PM" term="%2224615913%22">24615913)</searchLink><br />Front Neurol. 2017 Sep 08;8:469. (PMID: <searchLink fieldCode="PM" term="%2228943860%22">28943860)</searchLink><br />Nat Genet. 1995 Oct;11(2):177-84. (PMID: <searchLink fieldCode="PM" term="%227550346%22">7550346)</searchLink><br />Science. 2019 Oct 25;366(6464):505-508. (PMID: <searchLink fieldCode="PM" term="%2231649201%22">31649201)</searchLink><br />Nature. 2019 Aug;572(7770):488-492. (PMID: <searchLink fieldCode="PM" term="%2231367042%22">31367042)</searchLink><br />Front Neurosci. 2019 Apr 24;13:310. (PMID: <searchLink fieldCode="PM" term="%2231068771%22">31068771)</searchLink><br />Nat Protoc. 2006;1(5):2406-15. (PMID: <searchLink fieldCode="PM" term="%2217406484%22">17406484)</searchLink><br />Clin Neuropharmacol. 2016 Jan-Feb;39(1):57-9. (PMID: <searchLink fieldCode="PM" term="%2226757306%22">26757306)</searchLink><br />Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2046-2049. (PMID: <searchLink fieldCode="PM" term="%2228893923%22">28893923)</searchLink><br />Transl Psychiatry. 2012 Dec 11;2:e202. (PMID: <searchLink fieldCode="PM" term="%2223233021%22">23233021)</searchLink><br />Front Cell Neurosci. 2017 Mar 07;11:54. (PMID: <searchLink fieldCode="PM" term="%2228326014%22">28326014)</searchLink><br />Neuropharmacology. 2018 Dec;143:186-204. (PMID: <searchLink fieldCode="PM" term="%2230248303%22">30248303)</searchLink><br />Chem. 2020 Aug 06;6(8):2073-2096. (PMID: <searchLink fieldCode="PM" term="%2232818158%22">32818158)</searchLink><br />Sci Rep. 2018 Feb 26;8(1):3602. (PMID: <searchLink fieldCode="PM" term="%2229483603%22">29483603)</searchLink><br />Transl Psychiatry. 2020 Jan 27;10(1):9. (PMID: <searchLink fieldCode="PM" term="%2232066666%22">32066666)</searchLink><br />Acta Paediatr. 2010 Dec;99(12):1885-8. (PMID: <searchLink fieldCode="PM" term="%2220608900%22">20608900)</searchLink><br />Trends Neurosci. 2017 Sep;40(9):536-554. (PMID: <searchLink fieldCode="PM" term="%2228818303%22">28818303)</searchLink><br />Schizophr Res. 2017 Jun;184:145-146. (PMID: <searchLink fieldCode="PM" term="%2227956008%22">27956008)</searchLink><br />Epilepsia. 2013 Jan;54(1):e9-12. (PMID: <searchLink fieldCode="PM" term="%2223061490%22">23061490)</searchLink><br />Acta Paediatr. 2013 Jun;102(6):e288-90. (PMID: <searchLink fieldCode="PM" term="%2223647528%22">23647528)</searchLink><br />J Am Acad Child Adolesc Psychiatry. 2021 Jul;60(7):865-876. (PMID: <searchLink fieldCode="PM" term="%2232730977%22">32730977)</searchLink><br />Epilepsy Behav. 2016 Jun;59:42-9. (PMID: <searchLink fieldCode="PM" term="%2227088517%22">27088517)</searchLink><br />Commun Biol. 2021 Feb 17;4(1):226. (PMID: <searchLink fieldCode="PM" term="%2233597714%22">33597714)</searchLink><br />J Med Chem. 2013 Jan 10;56(1):2-12. (PMID: <searchLink fieldCode="PM" term="%2223075026%22">23075026)</searchLink><br />Acta Paediatr. 2021 May;110(5):1548-1553. (PMID: <searchLink fieldCode="PM" term="%2233336381%22">33336381)</searchLink><br />Transl Psychiatry. 2017 Mar 14;7(3):e1056. (PMID: <searchLink fieldCode="PM" term="%2228291262%22">28291262)</searchLink><br />Cell Res. 2021 Apr;31(4):482-484. (PMID: <searchLink fieldCode="PM" term="%2233199848%22">33199848)</searchLink><br />Ann Neurol. 2021 Feb;89(2):327-340. (PMID: <searchLink fieldCode="PM" term="%2233201535%22">33201535)</searchLink><br />Medicine (Baltimore). 2020 Jan;99(2):e18661. (PMID: <searchLink fieldCode="PM" term="%2231914053%22">31914053)</searchLink><br />Mamm Genome. 2011 Dec;22(11-12):685-91. (PMID: <searchLink fieldCode="PM" term="%2221953412%22">21953412)</searchLink><br />Clin Neuropharmacol. 2016 Mar-Apr;39(2):115-7. (PMID: <searchLink fieldCode="PM" term="%2226966887%22">26966887)</searchLink><br />J Otol. 2016 Dec;11(4):145-156. (PMID: <searchLink fieldCode="PM" term="%2229937824%22">29937824)</searchLink><br />Chem Biol Drug Des. 2006 May;67(5):370-2. (PMID: <searchLink fieldCode="PM" term="%2216784462%22">16784462)</searchLink><br />J Child Adolesc Psychopharmacol. 2015 Sep;25(7):585-8. (PMID: <searchLink fieldCode="PM" term="%2226258842%22">26258842)</searchLink><br />PLoS One. 2012;7(4):e35373. (PMID: <searchLink fieldCode="PM" term="%2222506078%22">22506078)</searchLink><br />Front Cell Neurosci. 2014 May 22;8:119. (PMID: <searchLink fieldCode="PM" term="%2224904277%22">24904277)</searchLink><br />Ren Fail. 2014 Aug;36(7):1051-5. (PMID: <searchLink fieldCode="PM" term="%2224940940%22">24940940)</searchLink><br />J Clin Neurosci. 2020 Nov;81:477-484. (PMID: <searchLink fieldCode="PM" term="%2233222966%22">33222966)</searchLink><br />Mol Autism. 2020 May 7;11(1):30. (PMID: <searchLink fieldCode="PM" term="%2232381101%22">32381101)</searchLink><br />Autism. 2015 Feb;19(2):149-57. (PMID: <searchLink fieldCode="PM" term="%2224343334%22">24343334)</searchLink><br />Nat Commun. 2020 Feb 21;11(1):1016. (PMID: <searchLink fieldCode="PM" term="%2232081947%22">32081947)</searchLink><br />Elife. 2020 Apr 14;9:. (PMID: <searchLink fieldCode="PM" term="%2232286222%22">32286222)</searchLink><br />Tunis Med. 2019 Aug - Sep;97(8-9):971-977. (PMID: <searchLink fieldCode="PM" term="%2232173844%22">32173844)</searchLink><br />CNS Drugs. 2019 Mar;33(3):283-291. (PMID: <searchLink fieldCode="PM" term="%2230784026%22">30784026)</searchLink><br />BMJ Case Rep. 2014 Jan 31;2014:. (PMID: <searchLink fieldCode="PM" term="%2224488662%22">24488662)</searchLink><br />J Neurosci. 2007 May 9;27(19):5224-35. (PMID: <searchLink fieldCode="PM" term="%2217494709%22">17494709)</searchLink><br />Nat Med. 2015 Apr;21(4):318-26. (PMID: <searchLink fieldCode="PM" term="%2225774849%22">25774849)</searchLink><br />Pediatrics. 2015 Aug;136(2):e539-43. (PMID: <searchLink fieldCode="PM" term="%2226216321%22">26216321)</searchLink><br />Structure. 2020 Sep 1;28(9):1051-1060.e4. (PMID: <searchLink fieldCode="PM" term="%2232679039%22">32679039)</searchLink><br />Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5383-8. (PMID: <searchLink fieldCode="PM" term="%2219279215%22">19279215)</searchLink> )
Array ( [Name] => NumberCAS [Label] => Substance Nomenclature [Group] => ID [Data] => 0 (SLC12A2 protein, human)<br />0 (Solute Carrier Family 12, Member 2) )
Array ( [Name] => DateEntry [Label] => Entry Date(s) [Group] => Date [Data] => <i>Date Created: </i>20210617 <i>Date Completed: </i>20211006 <i>Latest Revision: </i>20211006 )
Array ( [Name] => DateUpdate [Label] => Update Code [Group] => Date [Data] => 20221216 )
Array ( [Name] => PubmedCentralID [Label] => PubMed Central ID [Group] => ID [Data] => PMC8311653 )
Array ( [Name] => DOI [Label] => DOI [Group] => ID [Data] => 10.1021/acs.jmedchem.1c00603 )
Array ( [Name] => AN [Label] => PMID [Group] => ID [Data] => 34137257 )
RecordInfo Array ( [BibEntity] => Array ( [Identifiers] => Array ( [0] => Array ( [Type] => doi [Value] => 10.1021/acs.jmedchem.1c00603 ) ) [Languages] => Array ( [0] => Array ( [Code] => eng [Text] => English ) ) [PhysicalDescription] => Array ( [Pagination] => Array ( [StartPage] => 10203 ) ) [Subjects] => Array ( [0] => Array ( [SubjectFull] => Animals [Type] => general ) [1] => Array ( [SubjectFull] => Cells, Cultured [Type] => general ) [2] => Array ( [SubjectFull] => Dose-Response Relationship, Drug [Type] => general ) [3] => Array ( [SubjectFull] => Down Syndrome metabolism [Type] => general ) [4] => Array ( [SubjectFull] => Female [Type] => general ) [5] => Array ( [SubjectFull] => HEK293 Cells [Type] => general ) [6] => Array ( [SubjectFull] => Humans [Type] => general ) [7] => Array ( [SubjectFull] => Male [Type] => general ) [8] => Array ( [SubjectFull] => Mice [Type] => general ) [9] => Array ( [SubjectFull] => Mice, Inbred C57BL [Type] => general ) [10] => Array ( [SubjectFull] => Mice, Transgenic [Type] => general ) [11] => Array ( [SubjectFull] => Molecular Structure [Type] => general ) [12] => Array ( [SubjectFull] => Structure-Activity Relationship [Type] => general ) [13] => Array ( [SubjectFull] => Down Syndrome drug therapy [Type] => general ) [14] => Array ( [SubjectFull] => Drug Design [Type] => general ) [15] => Array ( [SubjectFull] => Solute Carrier Family 12, Member 2 metabolism [Type] => general ) ) [Titles] => Array ( [0] => Array ( [TitleFull] => Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome. [Type] => main ) ) ) [BibRelationships] => Array ( [HasContributorRelationships] => Array ( [0] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Borgogno M ) ) ) [1] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Savardi A ) ) ) [2] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Manigrasso J ) ) ) [3] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Turci A ) ) ) [4] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Portioli C ) ) ) [5] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Ottonello G ) ) ) [6] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Bertozzi SM ) ) ) [7] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Armirotti A ) ) ) [8] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Contestabile A ) ) ) [9] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Cancedda L ) ) ) [10] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => De Vivo M ) ) ) ) [IsPartOfRelationships] => Array ( [0] => Array ( [BibEntity] => Array ( [Dates] => Array ( [0] => Array ( [D] => 22 [M] => 07 [Text] => 2021 Jul 22 [Type] => published [Y] => 2021 ) ) [Identifiers] => Array ( [0] => Array ( [Type] => issn-electronic [Value] => 1520-4804 ) ) [Numbering] => Array ( [0] => Array ( [Type] => volume [Value] => 64 ) [1] => Array ( [Type] => issue [Value] => 14 ) ) [Titles] => Array ( [0] => Array ( [TitleFull] => Journal of medicinal chemistry [Type] => main ) ) ) ) ) ) )
IllustrationInfo