Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3
[Display omitted] Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treat...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2015-08, Vol.23 (15), p.4871-4883 |
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| creator | Nakajima, Yutaka Inoue, Takayuki Nakai, Kazuo Mukoyoshi, Koichiro Hamaguchi, Hisao Hatanaka, Keiko Sasaki, Hiroshi Tanaka, Akira Takahashi, Fumie Kunikawa, Shigeki Usuda, Hiroyuki Moritomo, Ayako Higashi, Yasuyuki Inami, Masamichi Shirakami, Shohei |
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Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model. |
| doi_str_mv | 10.1016/j.bmc.2015.05.034 |
| format | Article |
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Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2015.05.034</identifier><identifier>PMID: 26071372</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Administration, Oral ; Amides - chemistry ; Amides - pharmacokinetics ; Amides - therapeutic use ; Animals ; Binding Sites ; Cell Proliferation - drug effects ; Docking calculation ; Dogs ; Graft Rejection - prevention & control ; Half-Life ; Haplorhini ; hERG (human ether-a-go-go-related gene) ; Humans ; Immunologic Factors - chemical synthesis ; Immunologic Factors - pharmacology ; Immunologic Factors - therapeutic use ; Immunomodulator ; Interleukin-2 - metabolism ; JAK (Janus kinase) ; JAK3 inhibitor ; Janus Kinase 1 - antagonists & inhibitors ; Janus Kinase 1 - metabolism ; Janus Kinase 2 - antagonists & inhibitors ; Janus Kinase 2 - metabolism ; Janus Kinase 3 - antagonists & inhibitors ; Janus Kinase 3 - metabolism ; Male ; Microsomes, Liver - metabolism ; Molecular Docking Simulation ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - pharmacokinetics ; Protein Kinase Inhibitors - therapeutic use ; Protein Structure, Tertiary ; Pyridines - chemistry ; Rats ; Rats, Inbred Lew ; T-Lymphocytes - cytology ; T-Lymphocytes - drug effects ; T-Lymphocytes - metabolism ; Transplant rejection ; Transplantation, Heterotopic</subject><ispartof>Bioorganic & medicinal chemistry, 2015-08, Vol.23 (15), p.4871-4883</ispartof><rights>2015 Elsevier Ltd</rights><rights>Copyright © 2015 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c423t-cc2c872a4c98c271282a8a0f725ca9e3a0bf22fe55c4a4e33c4c7ac70f0644213</citedby><cites>FETCH-LOGICAL-c423t-cc2c872a4c98c271282a8a0f725ca9e3a0bf22fe55c4a4e33c4c7ac70f0644213</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089615004344$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26071372$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nakajima, Yutaka</creatorcontrib><creatorcontrib>Inoue, Takayuki</creatorcontrib><creatorcontrib>Nakai, Kazuo</creatorcontrib><creatorcontrib>Mukoyoshi, Koichiro</creatorcontrib><creatorcontrib>Hamaguchi, Hisao</creatorcontrib><creatorcontrib>Hatanaka, Keiko</creatorcontrib><creatorcontrib>Sasaki, Hiroshi</creatorcontrib><creatorcontrib>Tanaka, Akira</creatorcontrib><creatorcontrib>Takahashi, Fumie</creatorcontrib><creatorcontrib>Kunikawa, Shigeki</creatorcontrib><creatorcontrib>Usuda, Hiroyuki</creatorcontrib><creatorcontrib>Moritomo, Ayako</creatorcontrib><creatorcontrib>Higashi, Yasuyuki</creatorcontrib><creatorcontrib>Inami, Masamichi</creatorcontrib><creatorcontrib>Shirakami, Shohei</creatorcontrib><title>Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.</description><subject>Administration, Oral</subject><subject>Amides - chemistry</subject><subject>Amides - pharmacokinetics</subject><subject>Amides - therapeutic use</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Cell Proliferation - drug effects</subject><subject>Docking calculation</subject><subject>Dogs</subject><subject>Graft Rejection - prevention & control</subject><subject>Half-Life</subject><subject>Haplorhini</subject><subject>hERG (human ether-a-go-go-related gene)</subject><subject>Humans</subject><subject>Immunologic Factors - chemical synthesis</subject><subject>Immunologic Factors - pharmacology</subject><subject>Immunologic Factors - therapeutic use</subject><subject>Immunomodulator</subject><subject>Interleukin-2 - metabolism</subject><subject>JAK (Janus kinase)</subject><subject>JAK3 inhibitor</subject><subject>Janus Kinase 1 - antagonists & inhibitors</subject><subject>Janus Kinase 1 - metabolism</subject><subject>Janus Kinase 2 - antagonists & inhibitors</subject><subject>Janus Kinase 2 - metabolism</subject><subject>Janus Kinase 3 - antagonists & inhibitors</subject><subject>Janus Kinase 3 - metabolism</subject><subject>Male</subject><subject>Microsomes, Liver - metabolism</subject><subject>Molecular Docking Simulation</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - pharmacokinetics</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Protein Structure, Tertiary</subject><subject>Pyridines - chemistry</subject><subject>Rats</subject><subject>Rats, Inbred Lew</subject><subject>T-Lymphocytes - cytology</subject><subject>T-Lymphocytes - drug effects</subject><subject>T-Lymphocytes - metabolism</subject><subject>Transplant rejection</subject><subject>Transplantation, Heterotopic</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kctuFDEQRS0EIkPgA9ggL1nQE7_6YbGKIiCQSCyAFUKWu7o6eNRtD7a7lfkRvheHCVkilVQq6d6jqrqEvORsyxlvznbbfoatYLzeslJSPSIbrhpVSan5Y7Jhuukq1unmhDxLaccYE0rzp-RENKzlshUb8vvLweefmFyi1g8UVzstNrvgaRipDytOlF9W-0OMYQrfxRtZ9T_K5AbnsaorsLEPt3Z2A9IBo1uLd8XCSnQfMvr8lxqinaYDxXF0YMGFJVE3z4sPcxiWyeYQE8023mB2_oZ-Or-Sz8mT0U4JX9z3U_Lt_buvF5fV9ecPHy_OrytQQuYKQEDXCqtAdyBaLjphO8vGVtRgNUrL-lGIEesalFUoJShoLbRsZI1SgstT8vrI3cfwa8GUzewS4DRZj2VNwxutlWY110XKj1KIIaWIo9lHN9t4MJyZuzjMzpQ4zF0chpWSqnhe3eOXfsbhwfHv_0Xw9ijAcuTqMJoEDj3g4CJCNkNw_8H_AbNrnaw</recordid><startdate>20150801</startdate><enddate>20150801</enddate><creator>Nakajima, Yutaka</creator><creator>Inoue, Takayuki</creator><creator>Nakai, Kazuo</creator><creator>Mukoyoshi, Koichiro</creator><creator>Hamaguchi, Hisao</creator><creator>Hatanaka, Keiko</creator><creator>Sasaki, Hiroshi</creator><creator>Tanaka, Akira</creator><creator>Takahashi, Fumie</creator><creator>Kunikawa, Shigeki</creator><creator>Usuda, Hiroyuki</creator><creator>Moritomo, Ayako</creator><creator>Higashi, Yasuyuki</creator><creator>Inami, Masamichi</creator><creator>Shirakami, Shohei</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>20150801</creationdate><title>Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3</title><author>Nakajima, Yutaka ; Inoue, Takayuki ; Nakai, Kazuo ; Mukoyoshi, Koichiro ; Hamaguchi, Hisao ; Hatanaka, Keiko ; Sasaki, Hiroshi ; Tanaka, Akira ; Takahashi, Fumie ; Kunikawa, Shigeki ; Usuda, Hiroyuki ; Moritomo, Ayako ; Higashi, Yasuyuki ; Inami, Masamichi ; Shirakami, Shohei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c423t-cc2c872a4c98c271282a8a0f725ca9e3a0bf22fe55c4a4e33c4c7ac70f0644213</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Administration, Oral</topic><topic>Amides - chemistry</topic><topic>Amides - pharmacokinetics</topic><topic>Amides - therapeutic use</topic><topic>Animals</topic><topic>Binding Sites</topic><topic>Cell Proliferation - drug effects</topic><topic>Docking calculation</topic><topic>Dogs</topic><topic>Graft Rejection - prevention & control</topic><topic>Half-Life</topic><topic>Haplorhini</topic><topic>hERG (human ether-a-go-go-related gene)</topic><topic>Humans</topic><topic>Immunologic Factors - chemical synthesis</topic><topic>Immunologic Factors - pharmacology</topic><topic>Immunologic Factors - therapeutic use</topic><topic>Immunomodulator</topic><topic>Interleukin-2 - metabolism</topic><topic>JAK (Janus kinase)</topic><topic>JAK3 inhibitor</topic><topic>Janus Kinase 1 - antagonists & inhibitors</topic><topic>Janus Kinase 1 - metabolism</topic><topic>Janus Kinase 2 - antagonists & inhibitors</topic><topic>Janus Kinase 2 - metabolism</topic><topic>Janus Kinase 3 - antagonists & inhibitors</topic><topic>Janus Kinase 3 - metabolism</topic><topic>Male</topic><topic>Microsomes, Liver - metabolism</topic><topic>Molecular Docking Simulation</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - pharmacokinetics</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Protein Structure, Tertiary</topic><topic>Pyridines - chemistry</topic><topic>Rats</topic><topic>Rats, Inbred Lew</topic><topic>T-Lymphocytes - cytology</topic><topic>T-Lymphocytes - drug effects</topic><topic>T-Lymphocytes - metabolism</topic><topic>Transplant rejection</topic><topic>Transplantation, Heterotopic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nakajima, Yutaka</creatorcontrib><creatorcontrib>Inoue, Takayuki</creatorcontrib><creatorcontrib>Nakai, Kazuo</creatorcontrib><creatorcontrib>Mukoyoshi, Koichiro</creatorcontrib><creatorcontrib>Hamaguchi, Hisao</creatorcontrib><creatorcontrib>Hatanaka, Keiko</creatorcontrib><creatorcontrib>Sasaki, Hiroshi</creatorcontrib><creatorcontrib>Tanaka, Akira</creatorcontrib><creatorcontrib>Takahashi, Fumie</creatorcontrib><creatorcontrib>Kunikawa, Shigeki</creatorcontrib><creatorcontrib>Usuda, Hiroyuki</creatorcontrib><creatorcontrib>Moritomo, Ayako</creatorcontrib><creatorcontrib>Higashi, Yasuyuki</creatorcontrib><creatorcontrib>Inami, Masamichi</creatorcontrib><creatorcontrib>Shirakami, Shohei</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>Nakajima, Yutaka</au><au>Inoue, Takayuki</au><au>Nakai, Kazuo</au><au>Mukoyoshi, Koichiro</au><au>Hamaguchi, Hisao</au><au>Hatanaka, Keiko</au><au>Sasaki, Hiroshi</au><au>Tanaka, Akira</au><au>Takahashi, Fumie</au><au>Kunikawa, Shigeki</au><au>Usuda, Hiroyuki</au><au>Moritomo, Ayako</au><au>Higashi, Yasuyuki</au><au>Inami, Masamichi</au><au>Shirakami, Shohei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2015-08-01</date><risdate>2015</risdate><volume>23</volume><issue>15</issue><spage>4871</spage><epage>4883</epage><pages>4871-4883</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26071372</pmid><doi>10.1016/j.bmc.2015.05.034</doi><tpages>13</tpages></addata></record> |
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| subjects | Administration, Oral Amides - chemistry Amides - pharmacokinetics Amides - therapeutic use Animals Binding Sites Cell Proliferation - drug effects Docking calculation Dogs Graft Rejection - prevention & control Half-Life Haplorhini hERG (human ether-a-go-go-related gene) Humans Immunologic Factors - chemical synthesis Immunologic Factors - pharmacology Immunologic Factors - therapeutic use Immunomodulator Interleukin-2 - metabolism JAK (Janus kinase) JAK3 inhibitor Janus Kinase 1 - antagonists & inhibitors Janus Kinase 1 - metabolism Janus Kinase 2 - antagonists & inhibitors Janus Kinase 2 - metabolism Janus Kinase 3 - antagonists & inhibitors Janus Kinase 3 - metabolism Male Microsomes, Liver - metabolism Molecular Docking Simulation Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - therapeutic use Protein Structure, Tertiary Pyridines - chemistry Rats Rats, Inbred Lew T-Lymphocytes - cytology T-Lymphocytes - drug effects T-Lymphocytes - metabolism Transplant rejection Transplantation, Heterotopic |
| title | Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3 |
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