Exploration of Pyrido[3,4-<i>d</i>]pyrimidines as Antagonists of the Human Chemokine Receptor CXCR2
Upregulated CXCR2 signalling is found in numerous inflammatory, autoimmune and neurodegenerative diseases, as well as in cancer. Consequently, CXCR2 antagonism is a promising therapeutic strategy for treatment of these disorders. We previously identified, via scaffold hopping, a pyrido[3,4-<i>...
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| Format: | Article |
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MDPI AG
2023-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/5/2099 |
| _version_ | 1797614811402469376 |
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| author | Max Van Hoof Sandra Claes Katrijn Boon Tom Van Loy Dominique Schols Wim Dehaen Steven De Jonghe |
| author_facet | Max Van Hoof Sandra Claes Katrijn Boon Tom Van Loy Dominique Schols Wim Dehaen Steven De Jonghe |
| author_sort | Max Van Hoof |
| collection | DOAJ |
| description | Upregulated CXCR2 signalling is found in numerous inflammatory, autoimmune and neurodegenerative diseases, as well as in cancer. Consequently, CXCR2 antagonism is a promising therapeutic strategy for treatment of these disorders. We previously identified, via scaffold hopping, a pyrido[3,4-<i>d</i>]pyrimidine analogue as a promising CXCR2 antagonist with an IC<sub>50</sub> value of 0.11 µM in a kinetic fluorescence-based calcium mobilization assay. This study aims at exploring the structure–activity relationship (SAR) and improving the CXCR2 antagonistic potency of this pyrido[3,4-<i>d</i>]pyrimidine via systematic structural modifications of the substitution pattern. Almost all new analogues completely lacked the CXCR2 antagonism, the exception being a 6-furanyl-pyrido[3,4-<i>d</i>]pyrimidine analogue (compound <b>17b</b>) that is endowed with similar antagonistic potency as the original hit. |
| first_indexed | 2024-03-11T07:17:32Z |
| format | Article |
| id | doaj.art-460cbb8f3c3e4770be67e2c1f11062b4 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T07:17:32Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-460cbb8f3c3e4770be67e2c1f11062b42023-11-17T08:11:59ZengMDPI AGMolecules1420-30492023-02-01285209910.3390/molecules28052099Exploration of Pyrido[3,4-<i>d</i>]pyrimidines as Antagonists of the Human Chemokine Receptor CXCR2Max Van Hoof0Sandra Claes1Katrijn Boon2Tom Van Loy3Dominique Schols4Wim Dehaen5Steven De Jonghe6Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, BelgiumDepartment of Microbiology, Immunology and Transplantation—Laboratory of Virology and Chemotherapy, KU Leuven—Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, BelgiumDepartment of Microbiology, Immunology and Transplantation—Laboratory of Virology and Chemotherapy, KU Leuven—Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, BelgiumDepartment of Microbiology, Immunology and Transplantation—Laboratory of Virology and Chemotherapy, KU Leuven—Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, BelgiumDepartment of Microbiology, Immunology and Transplantation—Laboratory of Virology and Chemotherapy, KU Leuven—Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, BelgiumMolecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, BelgiumDepartment of Microbiology, Immunology and Transplantation—Laboratory of Virology and Chemotherapy, KU Leuven—Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, BelgiumUpregulated CXCR2 signalling is found in numerous inflammatory, autoimmune and neurodegenerative diseases, as well as in cancer. Consequently, CXCR2 antagonism is a promising therapeutic strategy for treatment of these disorders. We previously identified, via scaffold hopping, a pyrido[3,4-<i>d</i>]pyrimidine analogue as a promising CXCR2 antagonist with an IC<sub>50</sub> value of 0.11 µM in a kinetic fluorescence-based calcium mobilization assay. This study aims at exploring the structure–activity relationship (SAR) and improving the CXCR2 antagonistic potency of this pyrido[3,4-<i>d</i>]pyrimidine via systematic structural modifications of the substitution pattern. Almost all new analogues completely lacked the CXCR2 antagonism, the exception being a 6-furanyl-pyrido[3,4-<i>d</i>]pyrimidine analogue (compound <b>17b</b>) that is endowed with similar antagonistic potency as the original hit.https://www.mdpi.com/1420-3049/28/5/2099CXCR2 antagonistspyrido[3,4-<i>d</i>]pyrimidinesSAR study |
| spellingShingle | Max Van Hoof Sandra Claes Katrijn Boon Tom Van Loy Dominique Schols Wim Dehaen Steven De Jonghe Exploration of Pyrido[3,4-<i>d</i>]pyrimidines as Antagonists of the Human Chemokine Receptor CXCR2 Molecules CXCR2 antagonists pyrido[3,4-<i>d</i>]pyrimidines SAR study |
| title | Exploration of Pyrido[3,4-<i>d</i>]pyrimidines as Antagonists of the Human Chemokine Receptor CXCR2 |
| title_full | Exploration of Pyrido[3,4-<i>d</i>]pyrimidines as Antagonists of the Human Chemokine Receptor CXCR2 |
| title_fullStr | Exploration of Pyrido[3,4-<i>d</i>]pyrimidines as Antagonists of the Human Chemokine Receptor CXCR2 |
| title_full_unstemmed | Exploration of Pyrido[3,4-<i>d</i>]pyrimidines as Antagonists of the Human Chemokine Receptor CXCR2 |
| title_short | Exploration of Pyrido[3,4-<i>d</i>]pyrimidines as Antagonists of the Human Chemokine Receptor CXCR2 |
| title_sort | exploration of pyrido 3 4 i d i pyrimidines as antagonists of the human chemokine receptor cxcr2 |
| topic | CXCR2 antagonists pyrido[3,4-<i>d</i>]pyrimidines SAR study |
| url | https://www.mdpi.com/1420-3049/28/5/2099 |
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