Design, Synthesis, and Development of Pyrazolo[1,5-<i>a</i>]pyrimidine Derivatives as a Novel Series of Selective PI3K<i>δ</i> Inhibitors: Part II—Benzimidazole Derivatives
Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal em...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-07-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/15/8/927 |
| _version_ | 1797431843847405568 |
|---|---|
| author | Mariola Stypik Stanisław Michałek Nina Orłowska Marcin Zagozda Maciej Dziachan Martyna Banach Paweł Turowski Paweł Gunerka Daria Zdżalik-Bielecka Aleksandra Stańczak Urszula Kędzierska Krzysztof Mulewski Damian Smuga Wioleta Maruszak Lidia Gurba-Bryśkiewicz Arkadiusz Leniak Wojciech Pietruś Zbigniew Ochal Mateusz Mach Beata Zygmunt Jerzy Pieczykolan Krzysztof Dubiel Maciej Wieczorek |
| author_facet | Mariola Stypik Stanisław Michałek Nina Orłowska Marcin Zagozda Maciej Dziachan Martyna Banach Paweł Turowski Paweł Gunerka Daria Zdżalik-Bielecka Aleksandra Stańczak Urszula Kędzierska Krzysztof Mulewski Damian Smuga Wioleta Maruszak Lidia Gurba-Bryśkiewicz Arkadiusz Leniak Wojciech Pietruś Zbigniew Ochal Mateusz Mach Beata Zygmunt Jerzy Pieczykolan Krzysztof Dubiel Maciej Wieczorek |
| author_sort | Mariola Stypik |
| collection | DOAJ |
| description | Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: <i>α</i>, <i>β</i>, <i>γ</i>, <i>δ</i>) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis. In this work, we synthesized a library of benzimidazole derivatives of pyrazolo[1,5-<i>a</i>]pyrimidine representing a collection of new, potent, active, and selective inhibitors of PI3K<i>δ</i>, displaying IC<sub>50</sub> values ranging from 1.892 to 0.018 μM. Among all compounds obtained, CPL302415 (<b>6</b>) showed the highest activity (IC<sub>50</sub> value of 18 nM for PI3K<i>δ</i>), good selectivity (for PI3K<i>δ</i> relative to other PI3K isoforms: PI3K<i>α</i>/<i>δ</i> = 79; PI3K<i>β</i>/<i>δ</i> = 1415; PI3K<i>γ</i>/<i>δ</i> = 939), and promising physicochemical properties. As a lead compound synthesized on a relatively large scale, this structure is considered a potential future candidate for clinical trials in SLE treatment. |
| first_indexed | 2024-03-09T09:51:09Z |
| format | Article |
| id | doaj.art-a571ed7c657c4ae3a404d1e13d1d6daf |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T09:51:09Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-a571ed7c657c4ae3a404d1e13d1d6daf2023-12-02T00:08:45ZengMDPI AGPharmaceuticals1424-82472022-07-0115892710.3390/ph15080927Design, Synthesis, and Development of Pyrazolo[1,5-<i>a</i>]pyrimidine Derivatives as a Novel Series of Selective PI3K<i>δ</i> Inhibitors: Part II—Benzimidazole DerivativesMariola Stypik0Stanisław Michałek1Nina Orłowska2Marcin Zagozda3Maciej Dziachan4Martyna Banach5Paweł Turowski6Paweł Gunerka7Daria Zdżalik-Bielecka8Aleksandra Stańczak9Urszula Kędzierska10Krzysztof Mulewski11Damian Smuga12Wioleta Maruszak13Lidia Gurba-Bryśkiewicz14Arkadiusz Leniak15Wojciech Pietruś16Zbigniew Ochal17Mateusz Mach18Beata Zygmunt19Jerzy Pieczykolan20Krzysztof Dubiel21Maciej Wieczorek22Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandFaculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warsaw, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazun Nowy, PolandPhosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: <i>α</i>, <i>β</i>, <i>γ</i>, <i>δ</i>) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis. In this work, we synthesized a library of benzimidazole derivatives of pyrazolo[1,5-<i>a</i>]pyrimidine representing a collection of new, potent, active, and selective inhibitors of PI3K<i>δ</i>, displaying IC<sub>50</sub> values ranging from 1.892 to 0.018 μM. Among all compounds obtained, CPL302415 (<b>6</b>) showed the highest activity (IC<sub>50</sub> value of 18 nM for PI3K<i>δ</i>), good selectivity (for PI3K<i>δ</i> relative to other PI3K isoforms: PI3K<i>α</i>/<i>δ</i> = 79; PI3K<i>β</i>/<i>δ</i> = 1415; PI3K<i>γ</i>/<i>δ</i> = 939), and promising physicochemical properties. As a lead compound synthesized on a relatively large scale, this structure is considered a potential future candidate for clinical trials in SLE treatment.https://www.mdpi.com/1424-8247/15/8/927PI3K<i>δ</i> inhibitorsanti-inflammatory therapy5-benzimidazole-pyrazolo[1,5-<i>a</i>]pyrimidineCPL302415 |
| spellingShingle | Mariola Stypik Stanisław Michałek Nina Orłowska Marcin Zagozda Maciej Dziachan Martyna Banach Paweł Turowski Paweł Gunerka Daria Zdżalik-Bielecka Aleksandra Stańczak Urszula Kędzierska Krzysztof Mulewski Damian Smuga Wioleta Maruszak Lidia Gurba-Bryśkiewicz Arkadiusz Leniak Wojciech Pietruś Zbigniew Ochal Mateusz Mach Beata Zygmunt Jerzy Pieczykolan Krzysztof Dubiel Maciej Wieczorek Design, Synthesis, and Development of Pyrazolo[1,5-<i>a</i>]pyrimidine Derivatives as a Novel Series of Selective PI3K<i>δ</i> Inhibitors: Part II—Benzimidazole Derivatives Pharmaceuticals PI3K<i>δ</i> inhibitors anti-inflammatory therapy 5-benzimidazole-pyrazolo[1,5-<i>a</i>]pyrimidine CPL302415 |
| title | Design, Synthesis, and Development of Pyrazolo[1,5-<i>a</i>]pyrimidine Derivatives as a Novel Series of Selective PI3K<i>δ</i> Inhibitors: Part II—Benzimidazole Derivatives |
| title_full | Design, Synthesis, and Development of Pyrazolo[1,5-<i>a</i>]pyrimidine Derivatives as a Novel Series of Selective PI3K<i>δ</i> Inhibitors: Part II—Benzimidazole Derivatives |
| title_fullStr | Design, Synthesis, and Development of Pyrazolo[1,5-<i>a</i>]pyrimidine Derivatives as a Novel Series of Selective PI3K<i>δ</i> Inhibitors: Part II—Benzimidazole Derivatives |
| title_full_unstemmed | Design, Synthesis, and Development of Pyrazolo[1,5-<i>a</i>]pyrimidine Derivatives as a Novel Series of Selective PI3K<i>δ</i> Inhibitors: Part II—Benzimidazole Derivatives |
| title_short | Design, Synthesis, and Development of Pyrazolo[1,5-<i>a</i>]pyrimidine Derivatives as a Novel Series of Selective PI3K<i>δ</i> Inhibitors: Part II—Benzimidazole Derivatives |
| title_sort | design synthesis and development of pyrazolo 1 5 i a i pyrimidine derivatives as a novel series of selective pi3k i δ i inhibitors part ii benzimidazole derivatives |
| topic | PI3K<i>δ</i> inhibitors anti-inflammatory therapy 5-benzimidazole-pyrazolo[1,5-<i>a</i>]pyrimidine CPL302415 |
| url | https://www.mdpi.com/1424-8247/15/8/927 |
| work_keys_str_mv | AT mariolastypik designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT stanisławmichałek designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT ninaorłowska designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT marcinzagozda designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT maciejdziachan designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT martynabanach designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT pawełturowski designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT pawełgunerka designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT dariazdzalikbielecka designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT aleksandrastanczak designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT urszulakedzierska designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT krzysztofmulewski designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT damiansmuga designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT wioletamaruszak designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT lidiagurbabryskiewicz designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT arkadiuszleniak designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT wojciechpietrus designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT zbigniewochal designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT mateuszmach designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT beatazygmunt designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT jerzypieczykolan designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT krzysztofdubiel designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives AT maciejwieczorek designsynthesisanddevelopmentofpyrazolo15iaipyrimidinederivativesasanovelseriesofselectivepi3kidiinhibitorspartiibenzimidazolederivatives |