Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfu...

Autores
Van Zandt, Michael C.; Whitehouse, Darren L.; Golebiowski, Adam; Ji, Min Koo; Zhang, Mingbao; Beckett, R. Paul; Jagdmann, G. Erik; Ryder, Todd R.; Sheeler, Ryan; Andreoli, Monica; Conway, Bruce; Mahboubi, Keyvan; D’Angelo, Gerard; Mitschler, Andre; Cousido Siah, Alexandra; Ruiz, Frances X.; Howard, Eduardo Ignacio; Podjarny, Alberto Daniel; Schroeter, Hagen
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure−activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.
Fil: Van Zandt, Michael C.. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Whitehouse, Darren L.. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Golebiowski, Adam. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Ji, Min Koo. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Zhang, Mingbao. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Beckett, R. Paul. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Jagdmann, G. Erik. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Ryder, Todd R.. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Sheeler, Ryan. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Andreoli, Monica. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Conway, Bruce. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Mahboubi, Keyvan. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: D’Angelo, Gerard. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Mitschler, Andre. Université de Strasbourg; Francia
Fil: Cousido Siah, Alexandra. Université de Strasbourg; Francia
Fil: Ruiz, Frances X.. Université de Strasbourg; Francia
Fil: Howard, Eduardo Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina. Université de Strasbourg; Francia
Fil: Podjarny, Alberto Daniel. Université de Strasbourg; Francia
Fil: Schroeter, Hagen. Mars Incorporated; Estados Unidos
Materia
Human Arginases I And Ii
Inhibitors
Structure-Activity Relationships (Sar)
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/23649
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/23649
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion InjuryVan Zandt, Michael C.Whitehouse, Darren L.Golebiowski, AdamJi, Min KooZhang, MingbaoBeckett, R. PaulJagdmann, G. ErikRyder, Todd R.Sheeler, RyanAndreoli, MonicaConway, BruceMahboubi, KeyvanD’Angelo, GerardMitschler, AndreCousido Siah, AlexandraRuiz, Frances X.Howard, Eduardo IgnacioPodjarny, Alberto DanielSchroeter, HagenHuman Arginases I And IiInhibitorsStructure-Activity Relationships (Sar)https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure−activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.Fil: Van Zandt, Michael C.. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Whitehouse, Darren L.. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Golebiowski, Adam. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Ji, Min Koo. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Zhang, Mingbao. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Beckett, R. Paul. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Jagdmann, G. Erik. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Ryder, Todd R.. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Sheeler, Ryan. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Andreoli, Monica. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Conway, Bruce. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Mahboubi, Keyvan. Institutes for Pharmaceutical Discovery; Estados UnidosFil: D’Angelo, Gerard. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Mitschler, Andre. Université de Strasbourg; FranciaFil: Cousido Siah, Alexandra. Université de Strasbourg; FranciaFil: Ruiz, Frances X.. Université de Strasbourg; FranciaFil: Howard, Eduardo Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina. Université de Strasbourg; FranciaFil: Podjarny, Alberto Daniel. Université de Strasbourg; FranciaFil: Schroeter, Hagen. Mars Incorporated; Estados UnidosAmerican Chemical Society2013-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/23649Van Zandt, Michael C.; Whitehouse, Darren L.; Golebiowski, Adam; Ji, Min Koo; Zhang, Mingbao; et al.; Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury; American Chemical Society; Journal of Medicinal Chemistry; 56; 6; 3-2013; 2568-25800022-2623CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1021/jm400014cinfo:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/abs/10.1021/jm400014cinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-05-27T14:16:25Zoai:ri.conicet.gov.ar:11336/23649instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-05-27 14:16:25.673CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury
title Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury
spellingShingle Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury
Van Zandt, Michael C.
Human Arginases I And Ii
Inhibitors
Structure-Activity Relationships (Sar)
title_short Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury
title_full Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury
title_fullStr Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury
title_full_unstemmed Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury
title_sort Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury
dc.creator.none.fl_str_mv Van Zandt, Michael C.
Whitehouse, Darren L.
Golebiowski, Adam
Ji, Min Koo
Zhang, Mingbao
Beckett, R. Paul
Jagdmann, G. Erik
Ryder, Todd R.
Sheeler, Ryan
Andreoli, Monica
Conway, Bruce
Mahboubi, Keyvan
D’Angelo, Gerard
Mitschler, Andre
Cousido Siah, Alexandra
Ruiz, Frances X.
Howard, Eduardo Ignacio
Podjarny, Alberto Daniel
Schroeter, Hagen
author Van Zandt, Michael C.
author_facet Van Zandt, Michael C.
Whitehouse, Darren L.
Golebiowski, Adam
Ji, Min Koo
Zhang, Mingbao
Beckett, R. Paul
Jagdmann, G. Erik
Ryder, Todd R.
Sheeler, Ryan
Andreoli, Monica
Conway, Bruce
Mahboubi, Keyvan
D’Angelo, Gerard
Mitschler, Andre
Cousido Siah, Alexandra
Ruiz, Frances X.
Howard, Eduardo Ignacio
Podjarny, Alberto Daniel
Schroeter, Hagen
author_role author
author2 Whitehouse, Darren L.
Golebiowski, Adam
Ji, Min Koo
Zhang, Mingbao
Beckett, R. Paul
Jagdmann, G. Erik
Ryder, Todd R.
Sheeler, Ryan
Andreoli, Monica
Conway, Bruce
Mahboubi, Keyvan
D’Angelo, Gerard
Mitschler, Andre
Cousido Siah, Alexandra
Ruiz, Frances X.
Howard, Eduardo Ignacio
Podjarny, Alberto Daniel
Schroeter, Hagen
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Human Arginases I And Ii
Inhibitors
Structure-Activity Relationships (Sar)
topic Human Arginases I And Ii
Inhibitors
Structure-Activity Relationships (Sar)
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure−activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.
Fil: Van Zandt, Michael C.. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Whitehouse, Darren L.. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Golebiowski, Adam. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Ji, Min Koo. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Zhang, Mingbao. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Beckett, R. Paul. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Jagdmann, G. Erik. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Ryder, Todd R.. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Sheeler, Ryan. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Andreoli, Monica. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Conway, Bruce. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Mahboubi, Keyvan. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: D’Angelo, Gerard. Institutes for Pharmaceutical Discovery; Estados Unidos
Fil: Mitschler, Andre. Université de Strasbourg; Francia
Fil: Cousido Siah, Alexandra. Université de Strasbourg; Francia
Fil: Ruiz, Frances X.. Université de Strasbourg; Francia
Fil: Howard, Eduardo Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina. Université de Strasbourg; Francia
Fil: Podjarny, Alberto Daniel. Université de Strasbourg; Francia
Fil: Schroeter, Hagen. Mars Incorporated; Estados Unidos
description Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure−activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.
publishDate 2013
dc.date.none.fl_str_mv 2013-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/23649
Van Zandt, Michael C.; Whitehouse, Darren L.; Golebiowski, Adam; Ji, Min Koo; Zhang, Mingbao; et al.; Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury; American Chemical Society; Journal of Medicinal Chemistry; 56; 6; 3-2013; 2568-2580
0022-2623
CONICET Digital
CONICET
url http://hdl.handle.net/11336/23649
identifier_str_mv Van Zandt, Michael C.; Whitehouse, Darren L.; Golebiowski, Adam; Ji, Min Koo; Zhang, Mingbao; et al.; Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury; American Chemical Society; Journal of Medicinal Chemistry; 56; 6; 3-2013; 2568-2580
0022-2623
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1021/jm400014c
info:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/abs/10.1021/jm400014c
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.130638

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