Discovery of N‑(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)‑5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)‑2H‑tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis
Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and sel...
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| Veröffentlicht in: | Journal of medicinal chemistry 2016-01, Vol.59 (1), p.313-327 |
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| creator | Ruminski, Peter G Massa, Mark Strohbach, Joseph Hanau, Cathleen E Schmidt, Michelle Scholten, Jeffrey A Fletcher, Theresa R Hamper, Bruce C Carroll, Jeffery N Shieh, Huey S Caspers, Nicole Collins, Brandon Grapperhaus, Margaret Palmquist, Katherine E Collins, Joe Baldus, John E Hitchcock, Jeffrey Kleine, H. Peter Rogers, Michael D McDonald, Joseph Munie, Grace E Messing, Dean M Portolan, Silvia Whiteley, Laurence O Sunyer, Teresa Schnute, Mark E |
| description | Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures. |
| doi_str_mv | 10.1021/acs.jmedchem.5b01434 |
| format | Article |
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A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis</title><source>ACS Publications</source><source>MEDLINE</source><creator>Ruminski, Peter G ; Massa, Mark ; Strohbach, Joseph ; Hanau, Cathleen E ; Schmidt, Michelle ; Scholten, Jeffrey A ; Fletcher, Theresa R ; Hamper, Bruce C ; Carroll, Jeffery N ; Shieh, Huey S ; Caspers, Nicole ; Collins, Brandon ; Grapperhaus, Margaret ; Palmquist, Katherine E ; Collins, Joe ; Baldus, John E ; Hitchcock, Jeffrey ; Kleine, H. Peter ; Rogers, Michael D ; McDonald, Joseph ; Munie, Grace E ; Messing, Dean M ; Portolan, Silvia ; Whiteley, Laurence O ; Sunyer, Teresa ; Schnute, Mark E</creator><creatorcontrib>Ruminski, Peter G ; Massa, Mark ; Strohbach, Joseph ; Hanau, Cathleen E ; Schmidt, Michelle ; Scholten, Jeffrey A ; Fletcher, Theresa R ; Hamper, Bruce C ; Carroll, Jeffery N ; Shieh, Huey S ; Caspers, Nicole ; Collins, Brandon ; Grapperhaus, Margaret ; Palmquist, Katherine E ; Collins, Joe ; Baldus, John E ; Hitchcock, Jeffrey ; Kleine, H. Peter ; Rogers, Michael D ; McDonald, Joseph ; Munie, Grace E ; Messing, Dean M ; Portolan, Silvia ; Whiteley, Laurence O ; Sunyer, Teresa ; Schnute, Mark E</creatorcontrib><description>Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.5b01434</identifier><identifier>PMID: 26653735</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Cartilage, Articular - drug effects ; Cartilage, Articular - pathology ; Collagenases - drug effects ; Dogs ; Drug Design ; Humans ; Kidney - metabolism ; Macaca fascicularis ; Male ; Matrix Metalloproteinase 13 - drug effects ; Matrix Metalloproteinase Inhibitors - chemical synthesis ; Matrix Metalloproteinase Inhibitors - pharmacology ; Matrix Metalloproteinase Inhibitors - toxicity ; Models, Molecular ; Organic Anion Transporters, Sodium-Independent - metabolism ; Osteoarthritis - drug therapy ; Protein Binding ; Pyrimidines - chemical synthesis ; Pyrimidines - pharmacology ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship ; Tetrazoles - chemical synthesis ; Tetrazoles - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2016-01, Vol.59 (1), p.313-327</ispartof><rights>Copyright © 2015 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5b01434$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01434$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26653735$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ruminski, Peter G</creatorcontrib><creatorcontrib>Massa, Mark</creatorcontrib><creatorcontrib>Strohbach, Joseph</creatorcontrib><creatorcontrib>Hanau, Cathleen E</creatorcontrib><creatorcontrib>Schmidt, Michelle</creatorcontrib><creatorcontrib>Scholten, Jeffrey A</creatorcontrib><creatorcontrib>Fletcher, Theresa R</creatorcontrib><creatorcontrib>Hamper, Bruce C</creatorcontrib><creatorcontrib>Carroll, Jeffery N</creatorcontrib><creatorcontrib>Shieh, Huey S</creatorcontrib><creatorcontrib>Caspers, Nicole</creatorcontrib><creatorcontrib>Collins, Brandon</creatorcontrib><creatorcontrib>Grapperhaus, Margaret</creatorcontrib><creatorcontrib>Palmquist, Katherine E</creatorcontrib><creatorcontrib>Collins, Joe</creatorcontrib><creatorcontrib>Baldus, John E</creatorcontrib><creatorcontrib>Hitchcock, Jeffrey</creatorcontrib><creatorcontrib>Kleine, H. Peter</creatorcontrib><creatorcontrib>Rogers, Michael D</creatorcontrib><creatorcontrib>McDonald, Joseph</creatorcontrib><creatorcontrib>Munie, Grace E</creatorcontrib><creatorcontrib>Messing, Dean M</creatorcontrib><creatorcontrib>Portolan, Silvia</creatorcontrib><creatorcontrib>Whiteley, Laurence O</creatorcontrib><creatorcontrib>Sunyer, Teresa</creatorcontrib><creatorcontrib>Schnute, Mark E</creatorcontrib><title>Discovery of N‑(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)‑5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)‑2H‑tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures.</description><subject>Animals</subject><subject>Cartilage, Articular - drug effects</subject><subject>Cartilage, Articular - pathology</subject><subject>Collagenases - drug effects</subject><subject>Dogs</subject><subject>Drug Design</subject><subject>Humans</subject><subject>Kidney - metabolism</subject><subject>Macaca fascicularis</subject><subject>Male</subject><subject>Matrix Metalloproteinase 13 - drug effects</subject><subject>Matrix Metalloproteinase Inhibitors - chemical synthesis</subject><subject>Matrix Metalloproteinase Inhibitors - pharmacology</subject><subject>Matrix Metalloproteinase Inhibitors - toxicity</subject><subject>Models, Molecular</subject><subject>Organic Anion Transporters, Sodium-Independent - metabolism</subject><subject>Osteoarthritis - drug therapy</subject><subject>Protein Binding</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Structure-Activity Relationship</subject><subject>Tetrazoles - chemical synthesis</subject><subject>Tetrazoles - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kt1u1DAQhQMC0aXwBoB8mUr14r_87GVbWrZSyyJarqNJMiFeOfHK8a42veIVeMU-CQ67XNjWnPNpZM2ZKPrA2ZwzwT9DNczXHdZVi908KRlXUr2MZjwRjKqcqVfRjDEhqEiFPIneDsOaMSa5kG-iE5GmicxkMnvx8YseKrtDNxLbkG_Pv__Eit6YrXWWStqhb-1-LLF_Gs0ZTWksaBzH4uE8-XEW2ITG7Vi7gEzkhPBzRWtt99BTQYNw1AMrluHy6B08WUOTyQzIwd-MTne61j1SRStwZWgQapyTC7LUv1ozkgc0WHm9QwJ9TVYOTBAvtYUdaAOlQXIP3uk9uUcfPLtx1qPuYUDKJbntW11qbx1pwvEtku_B7r0GQx4dgu9CMU1gNXi04HzrtNfDu-h1A2bA98f3NPp5c_14taR3q6-3Vxd3FEQiPK1UXtUZK_lChhi4aBKeckTMatUInoMSLF1ki6pRKkMOooJUKgk5SsyBZbk8jT4d-m62ZYi02IRxgBuL_zkFgB2AkHqxtlvXh-8UnBXTKhT_xOMqFMdVkH8Bkj-thQ</recordid><startdate>20160114</startdate><enddate>20160114</enddate><creator>Ruminski, Peter G</creator><creator>Massa, Mark</creator><creator>Strohbach, Joseph</creator><creator>Hanau, Cathleen E</creator><creator>Schmidt, Michelle</creator><creator>Scholten, Jeffrey A</creator><creator>Fletcher, Theresa R</creator><creator>Hamper, Bruce C</creator><creator>Carroll, Jeffery N</creator><creator>Shieh, Huey S</creator><creator>Caspers, Nicole</creator><creator>Collins, Brandon</creator><creator>Grapperhaus, Margaret</creator><creator>Palmquist, Katherine E</creator><creator>Collins, Joe</creator><creator>Baldus, John E</creator><creator>Hitchcock, Jeffrey</creator><creator>Kleine, H. Peter</creator><creator>Rogers, Michael D</creator><creator>McDonald, Joseph</creator><creator>Munie, Grace E</creator><creator>Messing, Dean M</creator><creator>Portolan, Silvia</creator><creator>Whiteley, Laurence O</creator><creator>Sunyer, Teresa</creator><creator>Schnute, Mark E</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20160114</creationdate><title>Discovery of N‑(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)‑5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)‑2H‑tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis</title><author>Ruminski, Peter G ; Massa, Mark ; Strohbach, Joseph ; Hanau, Cathleen E ; Schmidt, Michelle ; Scholten, Jeffrey A ; Fletcher, Theresa R ; Hamper, Bruce C ; Carroll, Jeffery N ; Shieh, Huey S ; Caspers, Nicole ; Collins, Brandon ; Grapperhaus, Margaret ; Palmquist, Katherine E ; Collins, Joe ; Baldus, John E ; Hitchcock, Jeffrey ; Kleine, H. 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Peter</creatorcontrib><creatorcontrib>Rogers, Michael D</creatorcontrib><creatorcontrib>McDonald, Joseph</creatorcontrib><creatorcontrib>Munie, Grace E</creatorcontrib><creatorcontrib>Messing, Dean M</creatorcontrib><creatorcontrib>Portolan, Silvia</creatorcontrib><creatorcontrib>Whiteley, Laurence O</creatorcontrib><creatorcontrib>Sunyer, Teresa</creatorcontrib><creatorcontrib>Schnute, Mark E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ruminski, Peter G</au><au>Massa, Mark</au><au>Strohbach, Joseph</au><au>Hanau, Cathleen E</au><au>Schmidt, Michelle</au><au>Scholten, Jeffrey A</au><au>Fletcher, Theresa R</au><au>Hamper, Bruce C</au><au>Carroll, Jeffery N</au><au>Shieh, Huey S</au><au>Caspers, Nicole</au><au>Collins, Brandon</au><au>Grapperhaus, Margaret</au><au>Palmquist, Katherine E</au><au>Collins, Joe</au><au>Baldus, John E</au><au>Hitchcock, Jeffrey</au><au>Kleine, H. Peter</au><au>Rogers, Michael D</au><au>McDonald, Joseph</au><au>Munie, Grace E</au><au>Messing, Dean M</au><au>Portolan, Silvia</au><au>Whiteley, Laurence O</au><au>Sunyer, Teresa</au><au>Schnute, Mark E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of N‑(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)‑5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)‑2H‑tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2016-01-14</date><risdate>2016</risdate><volume>59</volume><issue>1</issue><spage>313</spage><epage>327</epage><pages>313-327</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>26653735</pmid><doi>10.1021/acs.jmedchem.5b01434</doi><tpages>15</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2016-01, Vol.59 (1), p.313-327 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_pubmed_primary_26653735 |
| source | ACS Publications; MEDLINE |
| subjects | Animals Cartilage, Articular - drug effects Cartilage, Articular - pathology Collagenases - drug effects Dogs Drug Design Humans Kidney - metabolism Macaca fascicularis Male Matrix Metalloproteinase 13 - drug effects Matrix Metalloproteinase Inhibitors - chemical synthesis Matrix Metalloproteinase Inhibitors - pharmacology Matrix Metalloproteinase Inhibitors - toxicity Models, Molecular Organic Anion Transporters, Sodium-Independent - metabolism Osteoarthritis - drug therapy Protein Binding Pyrimidines - chemical synthesis Pyrimidines - pharmacology Rats Rats, Sprague-Dawley Structure-Activity Relationship Tetrazoles - chemical synthesis Tetrazoles - pharmacology |
| title | Discovery of N‑(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)‑5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)‑2H‑tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis |
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