Discovery and biological evaluation of novel pyrazolopyridine derivatives as potent and orally available PI3Kδ inhibitors
[Display omitted] Phosphatidylinositol-3-kinase (PI3K)δ inhibition is one of the most attractive approaches to the treatment of autoimmune diseases and leukocyte malignancies. Through the exploration of pyrazolopyridine derivatives as potential PI3Kδ inhibitors, compound 12a was identified as a pote...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2018-05, Vol.26 (9), p.2410-2419 |
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| creator | Hamajima, Toshihiro Takahashi, Fumie Kato, Koji Mukoyoshi, Koichiro Yoshihara, Kousei Yamaki, Susumu Sugano, Yukihito Moritomo, Ayako Yamagami, Kaoru Yokoo, Koji Fukahori, Hidehiko |
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Phosphatidylinositol-3-kinase (PI3K)δ inhibition is one of the most attractive approaches to the treatment of autoimmune diseases and leukocyte malignancies. Through the exploration of pyrazolopyridine derivatives as potential PI3Kδ inhibitors, compound 12a was identified as a potent PI3Kδ inhibitor but suffered from poor oral exposure in mice. With a modified amide linkage group, compound 15a was developed as an orally available PI3Kδ inhibitor with reduced selectivity against other PI3Ks. To improve the trade-off between selectivity and PK profile, structure–activity relationship (SAR) studies of terminal substituents on the pyrolidine ring were conducted. As a result, we developed potent PI3Kδ inhibitors with good oral availability. In particular, the representative compound 15j showed excellent selectivity for PI3Kδ over other PI3Ks with good oral exposure in mice. |
| doi_str_mv | 10.1016/j.bmc.2018.03.042 |
| format | Article |
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Phosphatidylinositol-3-kinase (PI3K)δ inhibition is one of the most attractive approaches to the treatment of autoimmune diseases and leukocyte malignancies. Through the exploration of pyrazolopyridine derivatives as potential PI3Kδ inhibitors, compound 12a was identified as a potent PI3Kδ inhibitor but suffered from poor oral exposure in mice. With a modified amide linkage group, compound 15a was developed as an orally available PI3Kδ inhibitor with reduced selectivity against other PI3Ks. To improve the trade-off between selectivity and PK profile, structure–activity relationship (SAR) studies of terminal substituents on the pyrolidine ring were conducted. As a result, we developed potent PI3Kδ inhibitors with good oral availability. In particular, the representative compound 15j showed excellent selectivity for PI3Kδ over other PI3Ks with good oral exposure in mice.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2018.03.042</identifier><identifier>PMID: 29631787</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject><![CDATA[Administration, Oral ; Animals ; Female ; Humans ; Isoform selectivity ; Mice, Inbred BALB C ; Molecular Docking Simulation ; Molecular Structure ; Nuclear Proteins - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; PI3Kδinhibitor ; Protein Kinase Inhibitors - administration & dosage ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - pharmacokinetics ; Protein Kinase Inhibitors - pharmacology ; Pyrazoles - administration & dosage ; Pyrazoles - chemical synthesis ; Pyrazoles - pharmacokinetics ; Pyrazoles - pharmacology ; Pyrazolopyridine ; Pyridines - administration & dosage ; Pyridines - chemical synthesis ; Pyridines - pharmacokinetics ; Pyridines - pharmacology ; Stereoisomerism ; Structure-Activity Relationship ; Transcription Factors - antagonists & inhibitors]]></subject><ispartof>Bioorganic & medicinal chemistry, 2018-05, Vol.26 (9), p.2410-2419</ispartof><rights>2018 Elsevier Ltd</rights><rights>Copyright © 2018 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c353t-87c70d9fdf025dd3c6f11423a6ccebb444b6129f411de9e76e22c73107c3c16c3</citedby><cites>FETCH-LOGICAL-c353t-87c70d9fdf025dd3c6f11423a6ccebb444b6129f411de9e76e22c73107c3c16c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2018.03.042$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3548,27922,27923,45993</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29631787$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hamajima, Toshihiro</creatorcontrib><creatorcontrib>Takahashi, Fumie</creatorcontrib><creatorcontrib>Kato, Koji</creatorcontrib><creatorcontrib>Mukoyoshi, Koichiro</creatorcontrib><creatorcontrib>Yoshihara, Kousei</creatorcontrib><creatorcontrib>Yamaki, Susumu</creatorcontrib><creatorcontrib>Sugano, Yukihito</creatorcontrib><creatorcontrib>Moritomo, Ayako</creatorcontrib><creatorcontrib>Yamagami, Kaoru</creatorcontrib><creatorcontrib>Yokoo, Koji</creatorcontrib><creatorcontrib>Fukahori, Hidehiko</creatorcontrib><title>Discovery and biological evaluation of novel pyrazolopyridine derivatives as potent and orally available PI3Kδ inhibitors</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
Phosphatidylinositol-3-kinase (PI3K)δ inhibition is one of the most attractive approaches to the treatment of autoimmune diseases and leukocyte malignancies. Through the exploration of pyrazolopyridine derivatives as potential PI3Kδ inhibitors, compound 12a was identified as a potent PI3Kδ inhibitor but suffered from poor oral exposure in mice. With a modified amide linkage group, compound 15a was developed as an orally available PI3Kδ inhibitor with reduced selectivity against other PI3Ks. To improve the trade-off between selectivity and PK profile, structure–activity relationship (SAR) studies of terminal substituents on the pyrolidine ring were conducted. As a result, we developed potent PI3Kδ inhibitors with good oral availability. In particular, the representative compound 15j showed excellent selectivity for PI3Kδ over other PI3Ks with good oral exposure in mice.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Female</subject><subject>Humans</subject><subject>Isoform selectivity</subject><subject>Mice, Inbred BALB C</subject><subject>Molecular Docking Simulation</subject><subject>Molecular Structure</subject><subject>Nuclear Proteins - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>PI3Kδinhibitor</subject><subject>Protein Kinase Inhibitors - administration & dosage</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - pharmacokinetics</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Pyrazoles - administration & dosage</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - pharmacokinetics</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyrazolopyridine</subject><subject>Pyridines - administration & dosage</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - pharmacokinetics</subject><subject>Pyridines - pharmacology</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Transcription Factors - antagonists & inhibitors</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1O3DAURi1EBcPPA3SDvGST1Nc2TqKuKmgBgdQuytpy7JvikSee2plIw3P1OfpMGIZ2yepuzj3Sdwj5CKwGBurTsu5XtuYM2pqJmkm-RxYglayE6GCfLFin2oq1nTokRzkvGWNcdnBADnmnBDRtsyBPVz7bOGPaUjM62vsY4i9vTaA4m7Axk48jjQMdCxPoepvMUyHK9c6PSB0mPxdoxkxNpus44Ti9mmIyIRTpbHwwfUD641bc_f1D_fjoez_FlE_Ih8GEjKdv95g8fPv68_Kmuv9-fXv55b6y4kJMVdvYhrlucAPjF84JqwYAyYVR1mLfSyl7BbwbJIDDDhuFnNtGAGussKCsOCbnO-86xd8bzJNelc0YghkxbrLmjIuGK2h5QWGH2hRzTjjodfIrk7YamH5Jrpe6JNcvyTUTuiQvP2dv-k2_Qvf_41_jAnzeAVhGzh6TztbjaNH5hHbSLvp39M-6SJTP</recordid><startdate>20180515</startdate><enddate>20180515</enddate><creator>Hamajima, Toshihiro</creator><creator>Takahashi, Fumie</creator><creator>Kato, Koji</creator><creator>Mukoyoshi, Koichiro</creator><creator>Yoshihara, Kousei</creator><creator>Yamaki, Susumu</creator><creator>Sugano, Yukihito</creator><creator>Moritomo, Ayako</creator><creator>Yamagami, Kaoru</creator><creator>Yokoo, Koji</creator><creator>Fukahori, Hidehiko</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20180515</creationdate><title>Discovery and biological evaluation of novel pyrazolopyridine derivatives as potent and orally available PI3Kδ inhibitors</title><author>Hamajima, Toshihiro ; Takahashi, Fumie ; Kato, Koji ; Mukoyoshi, Koichiro ; Yoshihara, Kousei ; Yamaki, Susumu ; Sugano, Yukihito ; Moritomo, Ayako ; Yamagami, Kaoru ; Yokoo, Koji ; Fukahori, Hidehiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-87c70d9fdf025dd3c6f11423a6ccebb444b6129f411de9e76e22c73107c3c16c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Female</topic><topic>Humans</topic><topic>Isoform selectivity</topic><topic>Mice, Inbred BALB C</topic><topic>Molecular Docking Simulation</topic><topic>Molecular Structure</topic><topic>Nuclear Proteins - antagonists & inhibitors</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>PI3Kδinhibitor</topic><topic>Protein Kinase Inhibitors - administration & dosage</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - pharmacokinetics</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Pyrazoles - administration & dosage</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - pharmacokinetics</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyrazolopyridine</topic><topic>Pyridines - administration & dosage</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - pharmacokinetics</topic><topic>Pyridines - pharmacology</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Transcription Factors - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hamajima, Toshihiro</creatorcontrib><creatorcontrib>Takahashi, Fumie</creatorcontrib><creatorcontrib>Kato, Koji</creatorcontrib><creatorcontrib>Mukoyoshi, Koichiro</creatorcontrib><creatorcontrib>Yoshihara, Kousei</creatorcontrib><creatorcontrib>Yamaki, Susumu</creatorcontrib><creatorcontrib>Sugano, Yukihito</creatorcontrib><creatorcontrib>Moritomo, Ayako</creatorcontrib><creatorcontrib>Yamagami, Kaoru</creatorcontrib><creatorcontrib>Yokoo, Koji</creatorcontrib><creatorcontrib>Fukahori, Hidehiko</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hamajima, Toshihiro</au><au>Takahashi, Fumie</au><au>Kato, Koji</au><au>Mukoyoshi, Koichiro</au><au>Yoshihara, Kousei</au><au>Yamaki, Susumu</au><au>Sugano, Yukihito</au><au>Moritomo, Ayako</au><au>Yamagami, Kaoru</au><au>Yokoo, Koji</au><au>Fukahori, Hidehiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery and biological evaluation of novel pyrazolopyridine derivatives as potent and orally available PI3Kδ inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2018-05-15</date><risdate>2018</risdate><volume>26</volume><issue>9</issue><spage>2410</spage><epage>2419</epage><pages>2410-2419</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
Phosphatidylinositol-3-kinase (PI3K)δ inhibition is one of the most attractive approaches to the treatment of autoimmune diseases and leukocyte malignancies. Through the exploration of pyrazolopyridine derivatives as potential PI3Kδ inhibitors, compound 12a was identified as a potent PI3Kδ inhibitor but suffered from poor oral exposure in mice. With a modified amide linkage group, compound 15a was developed as an orally available PI3Kδ inhibitor with reduced selectivity against other PI3Ks. To improve the trade-off between selectivity and PK profile, structure–activity relationship (SAR) studies of terminal substituents on the pyrolidine ring were conducted. As a result, we developed potent PI3Kδ inhibitors with good oral availability. In particular, the representative compound 15j showed excellent selectivity for PI3Kδ over other PI3Ks with good oral exposure in mice.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>29631787</pmid><doi>10.1016/j.bmc.2018.03.042</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Bioorganic & medicinal chemistry, 2018-05, Vol.26 (9), p.2410-2419 |
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| language | eng |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Administration, Oral Animals Female Humans Isoform selectivity Mice, Inbred BALB C Molecular Docking Simulation Molecular Structure Nuclear Proteins - antagonists & inhibitors Phosphatidylinositol 3-Kinases - antagonists & inhibitors PI3Kδinhibitor Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Pyrazoles - administration & dosage Pyrazoles - chemical synthesis Pyrazoles - pharmacokinetics Pyrazoles - pharmacology Pyrazolopyridine Pyridines - administration & dosage Pyridines - chemical synthesis Pyridines - pharmacokinetics Pyridines - pharmacology Stereoisomerism Structure-Activity Relationship Transcription Factors - antagonists & inhibitors |
| title | Discovery and biological evaluation of novel pyrazolopyridine derivatives as potent and orally available PI3Kδ inhibitors |
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