Synthesis and biological evaluation of novel orally available 1-phenyl-6-aminouracils containing dimethyldihydrobenzofuranol structure for the treatment of allergic skin diseases
[Display omitted] We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2016-02, Vol.26 (4), p.1292-1295 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Tobe, Masanori Tsuboi, Katsunori Hasegawa, Futoshi Fujiwara, Norio Inoue, Yoshifumi Isobe, Masakazu Isobe, Yoshiaki |
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We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery of 13d bearing a 3-methyl group at the 1-phenyl group as a promising compound. Compound 13d, having good in vitro ADME profile and moderate oral bioavailability in mice, showed potent anti-inflammatory activity against hapten-induced contact hypersensitivity reaction in mice following topical and oral administration. The effects of 13d were equipotent to that of tacrolimus or prednisolone. In addition, compound 13d, having potent hydroxyl radical-scavenging activity, showed more potent suppressive effect on substance P-induced pruritus in mice than oxatomide. |
| doi_str_mv | 10.1016/j.bmcl.2016.01.019 |
| format | Article |
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We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery of 13d bearing a 3-methyl group at the 1-phenyl group as a promising compound. Compound 13d, having good in vitro ADME profile and moderate oral bioavailability in mice, showed potent anti-inflammatory activity against hapten-induced contact hypersensitivity reaction in mice following topical and oral administration. The effects of 13d were equipotent to that of tacrolimus or prednisolone. In addition, compound 13d, having potent hydroxyl radical-scavenging activity, showed more potent suppressive effect on substance P-induced pruritus in mice than oxatomide.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2016.01.019</identifier><identifier>PMID: 26786694</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>1-Phenyl-6-aminouracils ; Administration, Oral ; Animals ; Anti-Inflammatory Agents - chemical synthesis ; Anti-Inflammatory Agents - pharmacokinetics ; Anti-Inflammatory Agents - therapeutic use ; Benzofurans - chemistry ; Cell Line, Tumor ; Cell Membrane Permeability ; Contact hypersensitivity reaction ; CX-659S ; Dermatitis, Atopic - drug therapy ; Dermatitis, Atopic - pathology ; Dimethyldihydrobenzofuranol ; Half-Life ; Humans ; Mice ; Microsomes - metabolism ; Pruritus ; Pruritus - drug therapy ; Rats ; Uracil - analogs & derivatives ; Uracil - chemistry ; Uracil - pharmacokinetics ; Uracil - therapeutic use</subject><ispartof>Bioorganic & medicinal chemistry letters, 2016-02, Vol.26 (4), p.1292-1295</ispartof><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c525t-470ce51f9e8ada5926a53b62956a1d6e8db8301c91ce94478ad44b175fd9554e3</citedby><cites>FETCH-LOGICAL-c525t-470ce51f9e8ada5926a53b62956a1d6e8db8301c91ce94478ad44b175fd9554e3</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.2016.01.019$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27928,27929,45999</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26786694$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tobe, Masanori</creatorcontrib><creatorcontrib>Tsuboi, Katsunori</creatorcontrib><creatorcontrib>Hasegawa, Futoshi</creatorcontrib><creatorcontrib>Fujiwara, Norio</creatorcontrib><creatorcontrib>Inoue, Yoshifumi</creatorcontrib><creatorcontrib>Isobe, Masakazu</creatorcontrib><creatorcontrib>Isobe, Yoshiaki</creatorcontrib><title>Synthesis and biological evaluation of novel orally available 1-phenyl-6-aminouracils containing dimethyldihydrobenzofuranol structure for the treatment of allergic skin diseases</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery of 13d bearing a 3-methyl group at the 1-phenyl group as a promising compound. Compound 13d, having good in vitro ADME profile and moderate oral bioavailability in mice, showed potent anti-inflammatory activity against hapten-induced contact hypersensitivity reaction in mice following topical and oral administration. The effects of 13d were equipotent to that of tacrolimus or prednisolone. In addition, compound 13d, having potent hydroxyl radical-scavenging activity, showed more potent suppressive effect on substance P-induced pruritus in mice than oxatomide.</description><subject>1-Phenyl-6-aminouracils</subject><subject>Administration, Oral</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents - chemical synthesis</subject><subject>Anti-Inflammatory Agents - pharmacokinetics</subject><subject>Anti-Inflammatory Agents - therapeutic use</subject><subject>Benzofurans - chemistry</subject><subject>Cell Line, Tumor</subject><subject>Cell Membrane Permeability</subject><subject>Contact hypersensitivity reaction</subject><subject>CX-659S</subject><subject>Dermatitis, Atopic - drug therapy</subject><subject>Dermatitis, Atopic - pathology</subject><subject>Dimethyldihydrobenzofuranol</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Mice</subject><subject>Microsomes - metabolism</subject><subject>Pruritus</subject><subject>Pruritus - drug therapy</subject><subject>Rats</subject><subject>Uracil - analogs & derivatives</subject><subject>Uracil - chemistry</subject><subject>Uracil - pharmacokinetics</subject><subject>Uracil - therapeutic use</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc-KFDEQh4Mo7rj6Ah4kRy89Jj3pdAe8yOI_WPCggrdQnVTvZEwnY5IeaB_LJzTDrB5FKEgOX_2qqI-Q55xtOePy1WE7zsZv2_rfMl5LPSAbLqRodoJ1D8mGKcmaQYlvV-RJzgfGuGBCPCZXrewHKZXYkF-f11D2mF2mECwdXfTxzhnwFE_gFyguBhonGuIJPY0JvF8pnMB5GD1S3hz3GFbfyAZmF-KSwDifqYmhgAsu3FHrZiz71Vu3X22KI4afcapciJ7mkhZTloR0ionWPWhJCGXGUM5D6zBMdRuav7tQgzJCxvyUPJrAZ3x2_16Tr-_efrn50Nx-ev_x5s1tY7q2K43omcGOTwoHsNCpVkK3G2WrOgncShzsOOwYN4obVEL0lRJi5H03WdV1AnfX5OUl95jijwVz0bPLBr2HgHHJmveqHrgdBv4fqBTVCe93FW0vqEkx54STPiY3Q1o1Z_qsVR_0Was-a9WM11K16cV9_jLOaP-2_PFYgdcXAOtBTg6TzsZhMGhdQlO0je5f-b8Bctu5Dg</recordid><startdate>20160215</startdate><enddate>20160215</enddate><creator>Tobe, Masanori</creator><creator>Tsuboi, Katsunori</creator><creator>Hasegawa, Futoshi</creator><creator>Fujiwara, Norio</creator><creator>Inoue, Yoshifumi</creator><creator>Isobe, Masakazu</creator><creator>Isobe, Yoshiaki</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20160215</creationdate><title>Synthesis and biological evaluation of novel orally available 1-phenyl-6-aminouracils containing dimethyldihydrobenzofuranol structure for the treatment of allergic skin diseases</title><author>Tobe, Masanori ; Tsuboi, Katsunori ; Hasegawa, Futoshi ; Fujiwara, Norio ; Inoue, Yoshifumi ; Isobe, Masakazu ; Isobe, Yoshiaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c525t-470ce51f9e8ada5926a53b62956a1d6e8db8301c91ce94478ad44b175fd9554e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>1-Phenyl-6-aminouracils</topic><topic>Administration, Oral</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents - chemical synthesis</topic><topic>Anti-Inflammatory Agents - pharmacokinetics</topic><topic>Anti-Inflammatory Agents - therapeutic use</topic><topic>Benzofurans - chemistry</topic><topic>Cell Line, Tumor</topic><topic>Cell Membrane Permeability</topic><topic>Contact hypersensitivity reaction</topic><topic>CX-659S</topic><topic>Dermatitis, Atopic - drug therapy</topic><topic>Dermatitis, Atopic - pathology</topic><topic>Dimethyldihydrobenzofuranol</topic><topic>Half-Life</topic><topic>Humans</topic><topic>Mice</topic><topic>Microsomes - metabolism</topic><topic>Pruritus</topic><topic>Pruritus - drug therapy</topic><topic>Rats</topic><topic>Uracil - analogs & derivatives</topic><topic>Uracil - chemistry</topic><topic>Uracil - pharmacokinetics</topic><topic>Uracil - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tobe, Masanori</creatorcontrib><creatorcontrib>Tsuboi, Katsunori</creatorcontrib><creatorcontrib>Hasegawa, Futoshi</creatorcontrib><creatorcontrib>Fujiwara, Norio</creatorcontrib><creatorcontrib>Inoue, Yoshifumi</creatorcontrib><creatorcontrib>Isobe, Masakazu</creatorcontrib><creatorcontrib>Isobe, Yoshiaki</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><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tobe, Masanori</au><au>Tsuboi, Katsunori</au><au>Hasegawa, Futoshi</au><au>Fujiwara, Norio</au><au>Inoue, Yoshifumi</au><au>Isobe, Masakazu</au><au>Isobe, Yoshiaki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and biological evaluation of novel orally available 1-phenyl-6-aminouracils containing dimethyldihydrobenzofuranol structure for the treatment of allergic skin diseases</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2016-02-15</date><risdate>2016</risdate><volume>26</volume><issue>4</issue><spage>1292</spage><epage>1295</epage><pages>1292-1295</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery of 13d bearing a 3-methyl group at the 1-phenyl group as a promising compound. Compound 13d, having good in vitro ADME profile and moderate oral bioavailability in mice, showed potent anti-inflammatory activity against hapten-induced contact hypersensitivity reaction in mice following topical and oral administration. The effects of 13d were equipotent to that of tacrolimus or prednisolone. In addition, compound 13d, having potent hydroxyl radical-scavenging activity, showed more potent suppressive effect on substance P-induced pruritus in mice than oxatomide.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26786694</pmid><doi>10.1016/j.bmcl.2016.01.019</doi><tpages>4</tpages></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | 1-Phenyl-6-aminouracils Administration, Oral Animals Anti-Inflammatory Agents - chemical synthesis Anti-Inflammatory Agents - pharmacokinetics Anti-Inflammatory Agents - therapeutic use Benzofurans - chemistry Cell Line, Tumor Cell Membrane Permeability Contact hypersensitivity reaction CX-659S Dermatitis, Atopic - drug therapy Dermatitis, Atopic - pathology Dimethyldihydrobenzofuranol Half-Life Humans Mice Microsomes - metabolism Pruritus Pruritus - drug therapy Rats Uracil - analogs & derivatives Uracil - chemistry Uracil - pharmacokinetics Uracil - therapeutic use |
| title | Synthesis and biological evaluation of novel orally available 1-phenyl-6-aminouracils containing dimethyldihydrobenzofuranol structure for the treatment of allergic skin diseases |
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