Synthesis and structure-activity relationships of 3H-quinazolin-4-ones and 3H-pyrido[2,3-d]pyrimidin-4-ones as CXCR3 receptor antagonists

S. Storelli, D. Verzijl, J. Al-Badie, N. Elders, L. Bosch, H. Timmerman, M.J. Smit, I.J. De Esch, R. Leurs

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

CXC chemokine receptor-3 (CXCR3) is a G-protein coupled receptor (GPCR) predominantly expressed on activated T lymphocytes that promote Th1 responses. Previously, we described the 3H-quinazolin-4-one containing VUF 5834 (decanoic acid {1-[3-(4-cyano-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-ethyl}-(2- dimethylamino-ethyl)-amide) as a small-molecule CXCR3 antagonist with submicromolar affinity and as a lead structure for the development of CXCR3 antagonists. More recently, the related 3H-pyrido[2,3-d]pyrimidin-4-one compounds AMG 487 and NBI-74330 have been reported as nanomolar CXCR3 antagonists and these ligands are currently under clinical investigation. The aim of this study is to link the structure-activity relationship (SAR) of the previously published class of 3H-quinazolin-4-one containing CXCR3 ligands with these novel clinical candidates. From the modification of the lead structure VUF 5834 emerged the importance of the (4-fluoro-3-(trifluoromethyl)phenyl)acetyl and the 3-methylen-pyridine as substituents to improve the affinity at the human CXCR3 receptor, whereas other features are less important. The described molecules serve as tool to investigate the role of the CXCR3 receptor in various inflammatory conditions. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.
Original languageEnglish
Pages (from-to)281-91
JournalArchiv der Pharmazie
Volume340
Issue number6
DOIs
Publication statusPublished - 2007

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CXCR3 Receptors
Structure-Activity Relationship
Ligands
G-Protein-Coupled Receptors
4-hydroxyquinazoline
Amides
T-Lymphocytes

Cite this

@article{9cbee18829504f56af063c947ca3178b,
title = "Synthesis and structure-activity relationships of 3H-quinazolin-4-ones and 3H-pyrido[2,3-d]pyrimidin-4-ones as CXCR3 receptor antagonists",
abstract = "CXC chemokine receptor-3 (CXCR3) is a G-protein coupled receptor (GPCR) predominantly expressed on activated T lymphocytes that promote Th1 responses. Previously, we described the 3H-quinazolin-4-one containing VUF 5834 (decanoic acid {1-[3-(4-cyano-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-ethyl}-(2- dimethylamino-ethyl)-amide) as a small-molecule CXCR3 antagonist with submicromolar affinity and as a lead structure for the development of CXCR3 antagonists. More recently, the related 3H-pyrido[2,3-d]pyrimidin-4-one compounds AMG 487 and NBI-74330 have been reported as nanomolar CXCR3 antagonists and these ligands are currently under clinical investigation. The aim of this study is to link the structure-activity relationship (SAR) of the previously published class of 3H-quinazolin-4-one containing CXCR3 ligands with these novel clinical candidates. From the modification of the lead structure VUF 5834 emerged the importance of the (4-fluoro-3-(trifluoromethyl)phenyl)acetyl and the 3-methylen-pyridine as substituents to improve the affinity at the human CXCR3 receptor, whereas other features are less important. The described molecules serve as tool to investigate the role of the CXCR3 receptor in various inflammatory conditions. {\circledC} 2007 Wiley-VCH Verlag GmbH & Co. KGaA.",
author = "S. Storelli and D. Verzijl and J. Al-Badie and N. Elders and L. Bosch and H. Timmerman and M.J. Smit and {De Esch}, I.J. and R. Leurs",
year = "2007",
doi = "10.1002/ardp.200700037",
language = "English",
volume = "340",
pages = "281--91",
journal = "Archiv der Pharmazie",
issn = "0365-6233",
publisher = "Wiley-VCH Verlag",
number = "6",

}

Synthesis and structure-activity relationships of 3H-quinazolin-4-ones and 3H-pyrido[2,3-d]pyrimidin-4-ones as CXCR3 receptor antagonists. / Storelli, S.; Verzijl, D.; Al-Badie, J.; Elders, N.; Bosch, L.; Timmerman, H.; Smit, M.J.; De Esch, I.J.; Leurs, R.

In: Archiv der Pharmazie, Vol. 340, No. 6, 2007, p. 281-91.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Synthesis and structure-activity relationships of 3H-quinazolin-4-ones and 3H-pyrido[2,3-d]pyrimidin-4-ones as CXCR3 receptor antagonists

AU - Storelli, S.

AU - Verzijl, D.

AU - Al-Badie, J.

AU - Elders, N.

AU - Bosch, L.

AU - Timmerman, H.

AU - Smit, M.J.

AU - De Esch, I.J.

AU - Leurs, R.

PY - 2007

Y1 - 2007

N2 - CXC chemokine receptor-3 (CXCR3) is a G-protein coupled receptor (GPCR) predominantly expressed on activated T lymphocytes that promote Th1 responses. Previously, we described the 3H-quinazolin-4-one containing VUF 5834 (decanoic acid {1-[3-(4-cyano-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-ethyl}-(2- dimethylamino-ethyl)-amide) as a small-molecule CXCR3 antagonist with submicromolar affinity and as a lead structure for the development of CXCR3 antagonists. More recently, the related 3H-pyrido[2,3-d]pyrimidin-4-one compounds AMG 487 and NBI-74330 have been reported as nanomolar CXCR3 antagonists and these ligands are currently under clinical investigation. The aim of this study is to link the structure-activity relationship (SAR) of the previously published class of 3H-quinazolin-4-one containing CXCR3 ligands with these novel clinical candidates. From the modification of the lead structure VUF 5834 emerged the importance of the (4-fluoro-3-(trifluoromethyl)phenyl)acetyl and the 3-methylen-pyridine as substituents to improve the affinity at the human CXCR3 receptor, whereas other features are less important. The described molecules serve as tool to investigate the role of the CXCR3 receptor in various inflammatory conditions. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.

AB - CXC chemokine receptor-3 (CXCR3) is a G-protein coupled receptor (GPCR) predominantly expressed on activated T lymphocytes that promote Th1 responses. Previously, we described the 3H-quinazolin-4-one containing VUF 5834 (decanoic acid {1-[3-(4-cyano-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-ethyl}-(2- dimethylamino-ethyl)-amide) as a small-molecule CXCR3 antagonist with submicromolar affinity and as a lead structure for the development of CXCR3 antagonists. More recently, the related 3H-pyrido[2,3-d]pyrimidin-4-one compounds AMG 487 and NBI-74330 have been reported as nanomolar CXCR3 antagonists and these ligands are currently under clinical investigation. The aim of this study is to link the structure-activity relationship (SAR) of the previously published class of 3H-quinazolin-4-one containing CXCR3 ligands with these novel clinical candidates. From the modification of the lead structure VUF 5834 emerged the importance of the (4-fluoro-3-(trifluoromethyl)phenyl)acetyl and the 3-methylen-pyridine as substituents to improve the affinity at the human CXCR3 receptor, whereas other features are less important. The described molecules serve as tool to investigate the role of the CXCR3 receptor in various inflammatory conditions. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.

U2 - 10.1002/ardp.200700037

DO - 10.1002/ardp.200700037

M3 - Article

VL - 340

SP - 281

EP - 291

JO - Archiv der Pharmazie

JF - Archiv der Pharmazie

SN - 0365-6233

IS - 6

ER -