Towards the second generation of Boceprevir: Dithianes as an alternative P2 substituent for 2,2-dimethyl cycloproyl proline in HCV NS3 protease inhibitors
Hepatitis C (HCV) infection is a global health crisis leading to chronic liver disease. In our efforts towards a second generation HCV NS3 serine protease inhibitor with improved profile, we have undertaken SAR studies in various regions of Boceprevir including P2. Herein, we report the synthesis an...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010-03, Vol.20 (5), p.1689-1692 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Nair, Latha G. Bogen, Stephane Ruan, Sumei Pan, Weidong Pike, Russel Tong, Xiao Cheng, Kuo-Chi Guo, Zhuyan Doll, Ronald J. Njoroge, F. George |
| description | Hepatitis C (HCV) infection is a global health crisis leading to chronic liver disease. In our efforts towards a second generation HCV NS3 serine protease inhibitor with improved profile, we have undertaken SAR studies in various regions of Boceprevir including P2. Herein, we report the synthesis and structure–activity relationship studies of inhibitors with (
S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid
2 as P2 substituent replacing the (1
R,2
S,5
S)-6,6-dimethyl 3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The systematic investigation led to the discovery of highly potent inhibitor
25 (
K
i
∗
=
7
nM, EC
90
=
30
nM) with improved rat exposure of 2.56
μM
h. |
| doi_str_mv | 10.1016/j.bmcl.2010.01.037 |
| format | Article |
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S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid
2 as P2 substituent replacing the (1
R,2
S,5
S)-6,6-dimethyl 3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The systematic investigation led to the discovery of highly potent inhibitor
25 (
K
i
∗
=
7
nM, EC
90
=
30
nM) with improved rat exposure of 2.56
μM
h.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2010.01.037</identifier><identifier>PMID: 20149655</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Animals ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacokinetics ; Binding Sites ; Biological and medical sciences ; Computer Simulation ; Dithianes ; Glutarimides ; HCV protease ; Hepatitis C virus ; Humans ; Medical sciences ; Pharmacology. Drug treatments ; Proline - analogs & derivatives ; Proline - chemical synthesis ; Proline - chemistry ; Proline - pharmacokinetics ; Protease Inhibitors - chemical synthesis ; Protease Inhibitors - chemistry ; Protease Inhibitors - pharmacokinetics ; Quinolizines - chemistry ; Rats ; Structure-Activity Relationship ; Sulfur Compounds - chemistry ; Viral Nonstructural Proteins - antagonists & inhibitors ; Viral Nonstructural Proteins - metabolism</subject><ispartof>Bioorganic & medicinal chemistry letters, 2010-03, Vol.20 (5), p.1689-1692</ispartof><rights>2010</rights><rights>2015 INIST-CNRS</rights><rights>Copyright 2010. Published by Elsevier Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-4f2b9542403cc3a5a8013d8328dd7dde3f015760e496624e7c5a96549a3eda8b3</citedby><cites>FETCH-LOGICAL-c417t-4f2b9542403cc3a5a8013d8328dd7dde3f015760e496624e7c5a96549a3eda8b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X10000491$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22824773$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20149655$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nair, Latha G.</creatorcontrib><creatorcontrib>Bogen, Stephane</creatorcontrib><creatorcontrib>Ruan, Sumei</creatorcontrib><creatorcontrib>Pan, Weidong</creatorcontrib><creatorcontrib>Pike, Russel</creatorcontrib><creatorcontrib>Tong, Xiao</creatorcontrib><creatorcontrib>Cheng, Kuo-Chi</creatorcontrib><creatorcontrib>Guo, Zhuyan</creatorcontrib><creatorcontrib>Doll, Ronald J.</creatorcontrib><creatorcontrib>Njoroge, F. George</creatorcontrib><title>Towards the second generation of Boceprevir: Dithianes as an alternative P2 substituent for 2,2-dimethyl cycloproyl proline in HCV NS3 protease inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Hepatitis C (HCV) infection is a global health crisis leading to chronic liver disease. In our efforts towards a second generation HCV NS3 serine protease inhibitor with improved profile, we have undertaken SAR studies in various regions of Boceprevir including P2. Herein, we report the synthesis and structure–activity relationship studies of inhibitors with (
S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid
2 as P2 substituent replacing the (1
R,2
S,5
S)-6,6-dimethyl 3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The systematic investigation led to the discovery of highly potent inhibitor
25 (
K
i
∗
=
7
nM, EC
90
=
30
nM) with improved rat exposure of 2.56
μM
h.</description><subject>Animals</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacokinetics</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Computer Simulation</subject><subject>Dithianes</subject><subject>Glutarimides</subject><subject>HCV protease</subject><subject>Hepatitis C virus</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Proline - analogs & derivatives</subject><subject>Proline - chemical synthesis</subject><subject>Proline - chemistry</subject><subject>Proline - pharmacokinetics</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - pharmacokinetics</subject><subject>Quinolizines - chemistry</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><subject>Sulfur Compounds - chemistry</subject><subject>Viral Nonstructural Proteins - antagonists & inhibitors</subject><subject>Viral Nonstructural Proteins - metabolism</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkduqEzEUhoMo7lp9AS8kN-KNU3Ocg-wbrYctbFRwK96FTLLGpkyTmmQqfRWf1gyteqcQksXP9y_Wyo_QQ0pWlND62XbV78y4YqQIhK4Ib26hBRW1qLgg8jZakK4mVduJrxfoXkpbQqggQtxFF8UiulrKBfp5E37oaBPOG8AJTPAWfwMPUWcXPA4DfhkM7CMcXHyOX7m8cdpDwrocj_WYIfqCHgB_ZDhNfcouT-AzHkLE7CmrrNtB3hxHbI5mDPsYSlnu0XnAzuOr9Rf8_hOfpQw6zdrG9S6HmO6jO4MeEzw4v0v0-c3rm_VVdf3h7bv1i-vKCNrkSgys76RggnBjuJa6JZTblrPW2sZa4AOhsqkJlI1rJqAxUpfdRac5WN32fImenPqWGb5PkLLauWRgHMuiYUqqEbIhspPk_yTnpK27bibZiTQxpBRhUPvodjoeFSVqDk9t1RyemsNThKoSXjE9Oref-h3YP5bfaRXg8RnQyehxiNobl_5yrGWiKUMs0eWJg_JtBwdRJePAG7AugsnKBvevOX4Bx7C5Cw</recordid><startdate>20100301</startdate><enddate>20100301</enddate><creator>Nair, Latha G.</creator><creator>Bogen, Stephane</creator><creator>Ruan, Sumei</creator><creator>Pan, Weidong</creator><creator>Pike, Russel</creator><creator>Tong, Xiao</creator><creator>Cheng, Kuo-Chi</creator><creator>Guo, Zhuyan</creator><creator>Doll, Ronald J.</creator><creator>Njoroge, F. George</creator><general>Elsevier Ltd</general><general>Elsevier</general><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>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20100301</creationdate><title>Towards the second generation of Boceprevir: Dithianes as an alternative P2 substituent for 2,2-dimethyl cycloproyl proline in HCV NS3 protease inhibitors</title><author>Nair, Latha G. ; Bogen, Stephane ; Ruan, Sumei ; Pan, Weidong ; Pike, Russel ; Tong, Xiao ; Cheng, Kuo-Chi ; Guo, Zhuyan ; Doll, Ronald J. ; Njoroge, F. George</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-4f2b9542403cc3a5a8013d8328dd7dde3f015760e496624e7c5a96549a3eda8b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - chemical synthesis</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacokinetics</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Computer Simulation</topic><topic>Dithianes</topic><topic>Glutarimides</topic><topic>HCV protease</topic><topic>Hepatitis C virus</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Proline - analogs & derivatives</topic><topic>Proline - chemical synthesis</topic><topic>Proline - chemistry</topic><topic>Proline - pharmacokinetics</topic><topic>Protease Inhibitors - chemical synthesis</topic><topic>Protease Inhibitors - chemistry</topic><topic>Protease Inhibitors - pharmacokinetics</topic><topic>Quinolizines - chemistry</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><topic>Sulfur Compounds - chemistry</topic><topic>Viral Nonstructural Proteins - antagonists & inhibitors</topic><topic>Viral Nonstructural Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nair, Latha G.</creatorcontrib><creatorcontrib>Bogen, Stephane</creatorcontrib><creatorcontrib>Ruan, Sumei</creatorcontrib><creatorcontrib>Pan, Weidong</creatorcontrib><creatorcontrib>Pike, Russel</creatorcontrib><creatorcontrib>Tong, Xiao</creatorcontrib><creatorcontrib>Cheng, Kuo-Chi</creatorcontrib><creatorcontrib>Guo, Zhuyan</creatorcontrib><creatorcontrib>Doll, Ronald J.</creatorcontrib><creatorcontrib>Njoroge, F. 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George</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Towards the second generation of Boceprevir: Dithianes as an alternative P2 substituent for 2,2-dimethyl cycloproyl proline in HCV NS3 protease inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2010-03-01</date><risdate>2010</risdate><volume>20</volume><issue>5</issue><spage>1689</spage><epage>1692</epage><pages>1689-1692</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Hepatitis C (HCV) infection is a global health crisis leading to chronic liver disease. In our efforts towards a second generation HCV NS3 serine protease inhibitor with improved profile, we have undertaken SAR studies in various regions of Boceprevir including P2. Herein, we report the synthesis and structure–activity relationship studies of inhibitors with (
S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid
2 as P2 substituent replacing the (1
R,2
S,5
S)-6,6-dimethyl 3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The systematic investigation led to the discovery of highly potent inhibitor
25 (
K
i
∗
=
7
nM, EC
90
=
30
nM) with improved rat exposure of 2.56
μM
h.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>20149655</pmid><doi>10.1016/j.bmcl.2010.01.037</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2010-03, Vol.20 (5), p.1689-1692 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_745705950 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacokinetics Binding Sites Biological and medical sciences Computer Simulation Dithianes Glutarimides HCV protease Hepatitis C virus Humans Medical sciences Pharmacology. Drug treatments Proline - analogs & derivatives Proline - chemical synthesis Proline - chemistry Proline - pharmacokinetics Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacokinetics Quinolizines - chemistry Rats Structure-Activity Relationship Sulfur Compounds - chemistry Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - metabolism |
| title | Towards the second generation of Boceprevir: Dithianes as an alternative P2 substituent for 2,2-dimethyl cycloproyl proline in HCV NS3 protease inhibitors |
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