Design and synthesis of novel pyrimidine analogs as highly selective, non-covalent BTK inhibitors
[Display omitted] BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrate...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2018-01, Vol.28 (2), p.145-151 |
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| container_end_page | 151 |
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| container_issue | 2 |
| container_start_page | 145 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 28 |
| creator | Kawahata, Wataru Asami, Tokiko Irie, Takayuki Sawa, Masaaki |
| description | [Display omitted]
BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrated higher affinity to an unactivated conformation of BTK that resulted in an excellent kinase selectivity. Compound 25d showed a good oral bioavailability in mice, and significantly inhibits the PCA reaction in mice. |
| doi_str_mv | 10.1016/j.bmcl.2017.11.037 |
| format | Article |
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BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrated higher affinity to an unactivated conformation of BTK that resulted in an excellent kinase selectivity. Compound 25d showed a good oral bioavailability in mice, and significantly inhibits the PCA reaction in mice.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2017.11.037</identifier><identifier>PMID: 29198867</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Bruton’s tyrosine kinase ; Kinase inhibitor ; Kinase selectivity ; Passive cutaneous anaphylaxis ; Pyrimidine</subject><ispartof>Bioorganic & medicinal chemistry letters, 2018-01, Vol.28 (2), p.145-151</ispartof><rights>2017 Elsevier Ltd</rights><rights>Copyright © 2017 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-b6b3a8a68d66a345269eaadb1dca5e1ce4ab759903355ad50134654e9ba45e4b3</citedby><cites>FETCH-LOGICAL-c356t-b6b3a8a68d66a345269eaadb1dca5e1ce4ab759903355ad50134654e9ba45e4b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2017.11.037$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29198867$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kawahata, Wataru</creatorcontrib><creatorcontrib>Asami, Tokiko</creatorcontrib><creatorcontrib>Irie, Takayuki</creatorcontrib><creatorcontrib>Sawa, Masaaki</creatorcontrib><title>Design and synthesis of novel pyrimidine analogs as highly selective, non-covalent BTK inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrated higher affinity to an unactivated conformation of BTK that resulted in an excellent kinase selectivity. Compound 25d showed a good oral bioavailability in mice, and significantly inhibits the PCA reaction in mice.</description><subject>Bruton’s tyrosine kinase</subject><subject>Kinase inhibitor</subject><subject>Kinase selectivity</subject><subject>Passive cutaneous anaphylaxis</subject><subject>Pyrimidine</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp9kEtrGzEUhUVoaJy0fyCLomUXnYk0eswIumnT5kEC2aTQndDj2paRJWc0NvjfV8ZJll1dLnznwPkQuqSkpYTKq1Vr1y62HaF9S2lLWH-CZpRL3jBOxAc0I0qSZlD87xk6L2VFCOWE84_orFNUDYPsZ8j8ghIWCZvkcdmnaVnfgvMcp7yDiDf7MayDDwkqYWJeFGwKXobFMu5xgQhuCjv4VunUuLwzEdKEfz4_4JCWwYYpj-UTOp2bWODz671Af25-P1_fNY9Pt_fXPx4bx4ScGistM4ORg5fSMC46qcAYb6l3RgB1wI3thVKEMSGMF4QyLgUHZQ0XwC27QF-PvZsxv2yhTHodioMYTYK8LZqqvmNEdGSoaHdE3ZhLGWGuN3WmGfeaEn1Qq1f6oFYf1GpKdVVbQ19e-7d2Df498uayAt-PANSVuwCjLi5AcuDDWD1pn8P_-v8BrXGLgQ</recordid><startdate>20180115</startdate><enddate>20180115</enddate><creator>Kawahata, Wataru</creator><creator>Asami, Tokiko</creator><creator>Irie, Takayuki</creator><creator>Sawa, Masaaki</creator><general>Elsevier Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20180115</creationdate><title>Design and synthesis of novel pyrimidine analogs as highly selective, non-covalent BTK inhibitors</title><author>Kawahata, Wataru ; Asami, Tokiko ; Irie, Takayuki ; Sawa, Masaaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-b6b3a8a68d66a345269eaadb1dca5e1ce4ab759903355ad50134654e9ba45e4b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Bruton’s tyrosine kinase</topic><topic>Kinase inhibitor</topic><topic>Kinase selectivity</topic><topic>Passive cutaneous anaphylaxis</topic><topic>Pyrimidine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kawahata, Wataru</creatorcontrib><creatorcontrib>Asami, Tokiko</creatorcontrib><creatorcontrib>Irie, Takayuki</creatorcontrib><creatorcontrib>Sawa, Masaaki</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kawahata, Wataru</au><au>Asami, Tokiko</au><au>Irie, Takayuki</au><au>Sawa, Masaaki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design and synthesis of novel pyrimidine analogs as highly selective, non-covalent BTK inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2018-01-15</date><risdate>2018</risdate><volume>28</volume><issue>2</issue><spage>145</spage><epage>151</epage><pages>145-151</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrated higher affinity to an unactivated conformation of BTK that resulted in an excellent kinase selectivity. Compound 25d showed a good oral bioavailability in mice, and significantly inhibits the PCA reaction in mice.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>29198867</pmid><doi>10.1016/j.bmcl.2017.11.037</doi><tpages>7</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2018-01, Vol.28 (2), p.145-151 |
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| language | eng |
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| source | Elsevier ScienceDirect Journals Complete |
| subjects | Bruton’s tyrosine kinase Kinase inhibitor Kinase selectivity Passive cutaneous anaphylaxis Pyrimidine |
| title | Design and synthesis of novel pyrimidine analogs as highly selective, non-covalent BTK inhibitors |
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