The Use of a Penta-Deuterophenyl Substituent to Improve the Metabolic Stability of a Tyrosine Kinase Inhibitor

In cases in which a rapid metabolism is the cause of an unfavorable pharmacokinetic profile, it is important to determine the Sites of Metabolism (SoMs) of a molecule to introduce the necessary modifications to improve the stability of the compound. The substitution of hydrogen atoms by deuterium at...

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Authors: Dulsat, Júlia, Puig de la Bellacasa, Raimon, Borrell, Jose I.
Format: article
Publication Date:2024
Country:España
Institution:Universitat Ramon Llull (URL)
Repository:DAU Arxiu Digital de la Universitat Ramon Llull
OAI Identifier:oai:dau.url.edu:20.500.14342/5296
Online Access:http://hdl.handle.net/20.500.14342/5296
https://doi.org/10.3390/molecules29246042
Access Level:Open access
Keyword:metabolism
deuteration
pyrido[2,3-d]pyrimidin-7(8H)-one
tyrosine kinase inhibitor
612
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oai_identifier_str oai:dau.url.edu:20.500.14342/5296
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spelling The Use of a Penta-Deuterophenyl Substituent to Improve the Metabolic Stability of a Tyrosine Kinase InhibitorDulsat, JúliaPuig de la Bellacasa, RaimonBorrell, Jose I.metabolismdeuterationpyrido[2,3-d]pyrimidin-7(8H)-onetyrosine kinase inhibitor612In cases in which a rapid metabolism is the cause of an unfavorable pharmacokinetic profile, it is important to determine the Sites of Metabolism (SoMs) of a molecule to introduce the necessary modifications to improve the stability of the compound. The substitution of hydrogen atoms by deuterium atoms has been proposed to ameliorate such properties due to the greater stability of the C-D bonds. IQS016, bearing a 2-phenylamino substituent, is a compound previously described by our group with good biological activity as a discoidin domain receptor (DDR2) inhibitor but suffers from low metabolic stability determined in a test with rat-liver microsomes (less than 50% of the initial compound after 60 min). We have obtained the corresponding 2-(penta-deuterophenyl) analog (IQS016-d5) from aniline-2,3,4,5,6-d5 showing that it has a better metabolic stability than IQS016 and a higher inhibitory effect on isolated tyrosine kinase receptors but not a better 2D in vitro effect.info:eu-repo/semantics/publishedVersionMDPIUniversitat Ramon Llull. IQS202520252024info:eu-repo/semantics/article13 p.application/pdfhttp://hdl.handle.net/20.500.14342/5296https://doi.org/10.3390/molecules29246042reponame:DAU Arxiu Digital de la Universitat Ramon Llullinstname:Universitat Ramon Llull (URL)InglésMolecules. 2024;29(24):6042© L'autor/aAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:dau.url.edu:20.500.14342/52962026-06-21T06:40:37Z
dc.title.none.fl_str_mv The Use of a Penta-Deuterophenyl Substituent to Improve the Metabolic Stability of a Tyrosine Kinase Inhibitor
title The Use of a Penta-Deuterophenyl Substituent to Improve the Metabolic Stability of a Tyrosine Kinase Inhibitor
spellingShingle The Use of a Penta-Deuterophenyl Substituent to Improve the Metabolic Stability of a Tyrosine Kinase Inhibitor
Dulsat, Júlia
metabolism
deuteration
pyrido[2,3-d]pyrimidin-7(8H)-one
tyrosine kinase inhibitor
612
title_short The Use of a Penta-Deuterophenyl Substituent to Improve the Metabolic Stability of a Tyrosine Kinase Inhibitor
title_full The Use of a Penta-Deuterophenyl Substituent to Improve the Metabolic Stability of a Tyrosine Kinase Inhibitor
title_fullStr The Use of a Penta-Deuterophenyl Substituent to Improve the Metabolic Stability of a Tyrosine Kinase Inhibitor
title_full_unstemmed The Use of a Penta-Deuterophenyl Substituent to Improve the Metabolic Stability of a Tyrosine Kinase Inhibitor
title_sort The Use of a Penta-Deuterophenyl Substituent to Improve the Metabolic Stability of a Tyrosine Kinase Inhibitor
dc.creator.none.fl_str_mv Dulsat, Júlia
Puig de la Bellacasa, Raimon
Borrell, Jose I.
author Dulsat, Júlia
author_facet Dulsat, Júlia
Puig de la Bellacasa, Raimon
Borrell, Jose I.
author_role author
author2 Puig de la Bellacasa, Raimon
Borrell, Jose I.
author2_role author
author
dc.contributor.none.fl_str_mv Universitat Ramon Llull. IQS
dc.subject.none.fl_str_mv metabolism
deuteration
pyrido[2,3-d]pyrimidin-7(8H)-one
tyrosine kinase inhibitor
612
topic metabolism
deuteration
pyrido[2,3-d]pyrimidin-7(8H)-one
tyrosine kinase inhibitor
612
description In cases in which a rapid metabolism is the cause of an unfavorable pharmacokinetic profile, it is important to determine the Sites of Metabolism (SoMs) of a molecule to introduce the necessary modifications to improve the stability of the compound. The substitution of hydrogen atoms by deuterium atoms has been proposed to ameliorate such properties due to the greater stability of the C-D bonds. IQS016, bearing a 2-phenylamino substituent, is a compound previously described by our group with good biological activity as a discoidin domain receptor (DDR2) inhibitor but suffers from low metabolic stability determined in a test with rat-liver microsomes (less than 50% of the initial compound after 60 min). We have obtained the corresponding 2-(penta-deuterophenyl) analog (IQS016-d5) from aniline-2,3,4,5,6-d5 showing that it has a better metabolic stability than IQS016 and a higher inhibitory effect on isolated tyrosine kinase receptors but not a better 2D in vitro effect.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.14342/5296
https://doi.org/10.3390/molecules29246042
url http://hdl.handle.net/20.500.14342/5296
https://doi.org/10.3390/molecules29246042
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Molecules. 2024;29(24):6042
dc.rights.none.fl_str_mv © L'autor/a
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv © L'autor/a
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 13 p.
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:DAU Arxiu Digital de la Universitat Ramon Llull
instname:Universitat Ramon Llull (URL)
instname_str Universitat Ramon Llull (URL)
reponame_str DAU Arxiu Digital de la Universitat Ramon Llull
collection DAU Arxiu Digital de la Universitat Ramon Llull
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869419349044887552
score 15.811543

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