Development and Characterization of Biphenylsulfonamides as Novel Inhibitors of Bone Resorption
Increased osteoclastic bone resorption plays a central role in the pathogenesis of many bone diseases, and osteoclast inhibitors are the most widely used treatments for these diseases. We have identified and characterized a series of novel biphenylsulfonamide derivatives that have potent inhibitory...
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| Veröffentlicht in: | Journal of medicinal chemistry 2006-12, Vol.49 (25), p.7487-7492 |
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| container_title | Journal of medicinal chemistry |
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| creator | Greig, Iain R Idris, Aymen I Ralston, Stuart H van't Hof, Rob J |
| description | Increased osteoclastic bone resorption plays a central role in the pathogenesis of many bone diseases, and osteoclast inhibitors are the most widely used treatments for these diseases. We have identified and characterized a series of novel biphenylsulfonamide derivatives that have potent inhibitory effects on osteoclastic bone resorption in vitro and that prevent ovariectomy-induced bone loss in vivo. A number of aromatic substituted derivatives were prepared and a QSAR model was generated, which allowed accurate prediction of compound potency. Using this model, we have prepared compounds able to inhibit osteoclast formation and bone resorption in vitro at concentrations in the nanomolar range. One such compound, 55 (ABD295) (Greig, I. R.; Mohamed, A. I.; Ralston, S. H.; van't Hof, R. J. Alkyl Aryl Sulfonamides as Therapeutic Agents for the Treatment of Bone Conditions. GB Patent WO2005118528, 2005), fully reversed ovariectomy-induced bone loss in mice at a dose of 5 (mg/kg)/day. In conclusion, biphenylsulfonamides like 55 form a new class of potent antiresorptive agents with possible therapeutic use in diseases characterized by increased bone resorption. |
| doi_str_mv | 10.1021/jm051236m |
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We have identified and characterized a series of novel biphenylsulfonamide derivatives that have potent inhibitory effects on osteoclastic bone resorption in vitro and that prevent ovariectomy-induced bone loss in vivo. A number of aromatic substituted derivatives were prepared and a QSAR model was generated, which allowed accurate prediction of compound potency. Using this model, we have prepared compounds able to inhibit osteoclast formation and bone resorption in vitro at concentrations in the nanomolar range. One such compound, 55 (ABD295) (Greig, I. R.; Mohamed, A. I.; Ralston, S. H.; van't Hof, R. J. Alkyl Aryl Sulfonamides as Therapeutic Agents for the Treatment of Bone Conditions. GB Patent WO2005118528, 2005), fully reversed ovariectomy-induced bone loss in mice at a dose of 5 (mg/kg)/day. In conclusion, biphenylsulfonamides like 55 form a new class of potent antiresorptive agents with possible therapeutic use in diseases characterized by increased bone resorption.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm051236m</identifier><identifier>PMID: 17149877</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Biological and medical sciences ; Biphenyl Compounds - chemical synthesis ; Biphenyl Compounds - chemistry ; Biphenyl Compounds - pharmacology ; Bone Density - drug effects ; Bone Density Conservation Agents - chemical synthesis ; Bone Density Conservation Agents - chemistry ; Bone Density Conservation Agents - pharmacology ; Bone Resorption - drug therapy ; Bone Resorption - pathology ; Bone Resorption - physiopathology ; Bones, joints and connective tissue. Antiinflammatory agents ; Cell Survival - drug effects ; Cells, Cultured ; Humans ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Osteoblasts - cytology ; Osteoblasts - drug effects ; Osteoclasts - cytology ; Osteoclasts - drug effects ; Ovariectomy ; Pharmacology. Drug treatments ; Structure-Activity Relationship ; Sulfonamides - chemical synthesis ; Sulfonamides - chemistry ; Sulfonamides - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2006-12, Vol.49 (25), p.7487-7492</ispartof><rights>Copyright © 2006 American Chemical Society</rights><rights>2007 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a412t-c0b8f529cb8934f5bdfe60cb5a65010e55017fe545fd8bc545c7ff3ae66fa3513</citedby><cites>FETCH-LOGICAL-a412t-c0b8f529cb8934f5bdfe60cb5a65010e55017fe545fd8bc545c7ff3ae66fa3513</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm051236m$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm051236m$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18352556$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17149877$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Greig, Iain R</creatorcontrib><creatorcontrib>Idris, Aymen I</creatorcontrib><creatorcontrib>Ralston, Stuart H</creatorcontrib><creatorcontrib>van't Hof, Rob J</creatorcontrib><title>Development and Characterization of Biphenylsulfonamides as Novel Inhibitors of Bone Resorption</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Increased osteoclastic bone resorption plays a central role in the pathogenesis of many bone diseases, and osteoclast inhibitors are the most widely used treatments for these diseases. We have identified and characterized a series of novel biphenylsulfonamide derivatives that have potent inhibitory effects on osteoclastic bone resorption in vitro and that prevent ovariectomy-induced bone loss in vivo. A number of aromatic substituted derivatives were prepared and a QSAR model was generated, which allowed accurate prediction of compound potency. Using this model, we have prepared compounds able to inhibit osteoclast formation and bone resorption in vitro at concentrations in the nanomolar range. One such compound, 55 (ABD295) (Greig, I. R.; Mohamed, A. I.; Ralston, S. H.; van't Hof, R. J. Alkyl Aryl Sulfonamides as Therapeutic Agents for the Treatment of Bone Conditions. GB Patent WO2005118528, 2005), fully reversed ovariectomy-induced bone loss in mice at a dose of 5 (mg/kg)/day. In conclusion, biphenylsulfonamides like 55 form a new class of potent antiresorptive agents with possible therapeutic use in diseases characterized by increased bone resorption.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biphenyl Compounds - chemical synthesis</subject><subject>Biphenyl Compounds - chemistry</subject><subject>Biphenyl Compounds - pharmacology</subject><subject>Bone Density - drug effects</subject><subject>Bone Density Conservation Agents - chemical synthesis</subject><subject>Bone Density Conservation Agents - chemistry</subject><subject>Bone Density Conservation Agents - pharmacology</subject><subject>Bone Resorption - drug therapy</subject><subject>Bone Resorption - pathology</subject><subject>Bone Resorption - physiopathology</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Cell Survival - drug effects</subject><subject>Cells, Cultured</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Osteoblasts - cytology</subject><subject>Osteoblasts - drug effects</subject><subject>Osteoclasts - cytology</subject><subject>Osteoclasts - drug effects</subject><subject>Ovariectomy</subject><subject>Pharmacology. Drug treatments</subject><subject>Structure-Activity Relationship</subject><subject>Sulfonamides - chemical synthesis</subject><subject>Sulfonamides - chemistry</subject><subject>Sulfonamides - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0MFu1DAQBmALUdGlcOAFUC4gcQiM7djxHumWhVYVoFIkbpbjjLVeEjvYSUV5elJ21b1U4uI5-Jtfo5-QFxTeUmD03bYHQRmX_SOyoIJBWSmoHpMFAGMlk4wfk6c5bwGAz-wJOaY1rZaqrhdEn-ENdnHoMYyFCW2x2phk7IjJ_zGjj6GIrjj1wwbDbZenzsVget9iLkwuPsd5tzgPG9_4Mab8z8aAxRXmmIa79WfkyJku4_P9PCHf1x-uV5_Kyy8fz1fvL0tTUTaWFhrlBFvaRi155UTTOpRgG2GkAAoo5rd2KCrhWtXYedraOW5QSme4oPyEvN7lDin-mjCPuvfZYteZgHHKWirGFFD-X8iALSWDeoZvdtCmmHNCp4fke5NuNQV9V7u-r322L_ehU9Nje5D7nmfwag9MtqZzyQTr88EpLpgQcnblzvk84u_7f5N-alnzWujrr9_0Wl6oHxdXp3p9yDU2622cUphLfuDAv8e7pmg</recordid><startdate>20061214</startdate><enddate>20061214</enddate><creator>Greig, Iain R</creator><creator>Idris, Aymen I</creator><creator>Ralston, Stuart H</creator><creator>van't Hof, Rob J</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><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>7QO</scope><scope>7QP</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20061214</creationdate><title>Development and Characterization of Biphenylsulfonamides as Novel Inhibitors of Bone Resorption</title><author>Greig, Iain R ; Idris, Aymen I ; Ralston, Stuart H ; van't Hof, Rob J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a412t-c0b8f529cb8934f5bdfe60cb5a65010e55017fe545fd8bc545c7ff3ae66fa3513</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biphenyl Compounds - chemical synthesis</topic><topic>Biphenyl Compounds - chemistry</topic><topic>Biphenyl Compounds - pharmacology</topic><topic>Bone Density - drug effects</topic><topic>Bone Density Conservation Agents - chemical synthesis</topic><topic>Bone Density Conservation Agents - chemistry</topic><topic>Bone Density Conservation Agents - pharmacology</topic><topic>Bone Resorption - drug therapy</topic><topic>Bone Resorption - pathology</topic><topic>Bone Resorption - physiopathology</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>Cell Survival - drug effects</topic><topic>Cells, Cultured</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Osteoblasts - cytology</topic><topic>Osteoblasts - drug effects</topic><topic>Osteoclasts - cytology</topic><topic>Osteoclasts - drug effects</topic><topic>Ovariectomy</topic><topic>Pharmacology. Drug treatments</topic><topic>Structure-Activity Relationship</topic><topic>Sulfonamides - chemical synthesis</topic><topic>Sulfonamides - chemistry</topic><topic>Sulfonamides - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Greig, Iain R</creatorcontrib><creatorcontrib>Idris, Aymen I</creatorcontrib><creatorcontrib>Ralston, Stuart H</creatorcontrib><creatorcontrib>van't Hof, Rob J</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Greig, Iain R</au><au>Idris, Aymen I</au><au>Ralston, Stuart H</au><au>van't Hof, Rob J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development and Characterization of Biphenylsulfonamides as Novel Inhibitors of Bone Resorption</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2006-12-14</date><risdate>2006</risdate><volume>49</volume><issue>25</issue><spage>7487</spage><epage>7492</epage><pages>7487-7492</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Increased osteoclastic bone resorption plays a central role in the pathogenesis of many bone diseases, and osteoclast inhibitors are the most widely used treatments for these diseases. We have identified and characterized a series of novel biphenylsulfonamide derivatives that have potent inhibitory effects on osteoclastic bone resorption in vitro and that prevent ovariectomy-induced bone loss in vivo. A number of aromatic substituted derivatives were prepared and a QSAR model was generated, which allowed accurate prediction of compound potency. Using this model, we have prepared compounds able to inhibit osteoclast formation and bone resorption in vitro at concentrations in the nanomolar range. One such compound, 55 (ABD295) (Greig, I. R.; Mohamed, A. I.; Ralston, S. H.; van't Hof, R. J. Alkyl Aryl Sulfonamides as Therapeutic Agents for the Treatment of Bone Conditions. GB Patent WO2005118528, 2005), fully reversed ovariectomy-induced bone loss in mice at a dose of 5 (mg/kg)/day. In conclusion, biphenylsulfonamides like 55 form a new class of potent antiresorptive agents with possible therapeutic use in diseases characterized by increased bone resorption.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>17149877</pmid><doi>10.1021/jm051236m</doi><tpages>6</tpages></addata></record> |
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| subjects | Animals Biological and medical sciences Biphenyl Compounds - chemical synthesis Biphenyl Compounds - chemistry Biphenyl Compounds - pharmacology Bone Density - drug effects Bone Density Conservation Agents - chemical synthesis Bone Density Conservation Agents - chemistry Bone Density Conservation Agents - pharmacology Bone Resorption - drug therapy Bone Resorption - pathology Bone Resorption - physiopathology Bones, joints and connective tissue. Antiinflammatory agents Cell Survival - drug effects Cells, Cultured Humans Medical sciences Mice Mice, Inbred C57BL Osteoblasts - cytology Osteoblasts - drug effects Osteoclasts - cytology Osteoclasts - drug effects Ovariectomy Pharmacology. Drug treatments Structure-Activity Relationship Sulfonamides - chemical synthesis Sulfonamides - chemistry Sulfonamides - pharmacology |
| title | Development and Characterization of Biphenylsulfonamides as Novel Inhibitors of Bone Resorption |
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