Benzimidazolone as potent chymase inhibitor: Modulation of reactive metabolite formation in the hydrophobic (P 1) region
A new class of chymase inhibitor featuring a benzimidazolone core with an acid side chain and a P 1 hydrophobic moiety is described. Incubation of the lead compound with GSH resulted in the formation of a GSH conjugate on the benzothiophene P 1 moiety. Replacement of the benzothiophene with differen...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2011-08, Vol.21 (15), p.4533-4539 |
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| creator | Lo, Ho Yin Nemoto, Peter A. Kim, Jin Mi Hao, Ming-Hong Qian, Kevin C. Farrow, Neil A. Albaugh, Daniel R. Fowler, Danielle M. Schneiderman, Richard D. Michael August, E. Martin, Leslie Hill-Drzewi, Melissa Pullen, Steven S. Takahashi, Hidenori De Lombaert, Stéphane |
| description | A new class of chymase inhibitor featuring a benzimidazolone core with an acid side chain and a P
1 hydrophobic moiety is described. Incubation of the lead compound with GSH resulted in the formation of a GSH conjugate on the benzothiophene P
1 moiety. Replacement of the benzothiophene with different heterocyclic systems such as indoles and benzoisothiazole is feasible. Among the P
1 replacements, benzoisothiazole prevents the formation of GSH conjugate and an in silico analysis of oxidative potentials agreed with the experimental outcome. |
| doi_str_mv | 10.1016/j.bmcl.2011.05.126 |
| format | Article |
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1 hydrophobic moiety is described. Incubation of the lead compound with GSH resulted in the formation of a GSH conjugate on the benzothiophene P
1 moiety. Replacement of the benzothiophene with different heterocyclic systems such as indoles and benzoisothiazole is feasible. Among the P
1 replacements, benzoisothiazole prevents the formation of GSH conjugate and an in silico analysis of oxidative potentials agreed with the experimental outcome.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2011.05.126</identifier><identifier>PMID: 21733690</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Analytical, structural and metabolic biochemistry ; Benzimidazoles - chemistry ; Benzimidazoles - metabolism ; Benzimidazoles - pharmacology ; Benzoisothiazole ; Binding Sites ; Biological and medical sciences ; Cathepsin ; Chymase ; Chymases - antagonists & inhibitors ; Chymases - metabolism ; Crystallography, X-Ray ; Enzymes and enzyme inhibitors ; Fundamental and applied biological sciences. Psychology ; GSH ; Humans ; Hydrolases ; Hydrophobic and Hydrophilic Interactions ; Indole ; Medical sciences ; Miscellaneous ; Oxidation-Reduction ; Pharmacology. Drug treatments ; Protease Inhibitors - chemical synthesis ; Protease Inhibitors - chemistry ; Protease Inhibitors - pharmacology ; Protein Structure, Tertiary ; Serine protease ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2011-08, Vol.21 (15), p.4533-4539</ispartof><rights>2011 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-522b7ae17778d0108f0fe5a4cf4a70e1af81ddd0f25f8642fc87e487992afda23</citedby><cites>FETCH-LOGICAL-c417t-522b7ae17778d0108f0fe5a4cf4a70e1af81ddd0f25f8642fc87e487992afda23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X11007670$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24370299$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21733690$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lo, Ho Yin</creatorcontrib><creatorcontrib>Nemoto, Peter A.</creatorcontrib><creatorcontrib>Kim, Jin Mi</creatorcontrib><creatorcontrib>Hao, Ming-Hong</creatorcontrib><creatorcontrib>Qian, Kevin C.</creatorcontrib><creatorcontrib>Farrow, Neil A.</creatorcontrib><creatorcontrib>Albaugh, Daniel R.</creatorcontrib><creatorcontrib>Fowler, Danielle M.</creatorcontrib><creatorcontrib>Schneiderman, Richard D.</creatorcontrib><creatorcontrib>Michael August, E.</creatorcontrib><creatorcontrib>Martin, Leslie</creatorcontrib><creatorcontrib>Hill-Drzewi, Melissa</creatorcontrib><creatorcontrib>Pullen, Steven S.</creatorcontrib><creatorcontrib>Takahashi, Hidenori</creatorcontrib><creatorcontrib>De Lombaert, Stéphane</creatorcontrib><title>Benzimidazolone as potent chymase inhibitor: Modulation of reactive metabolite formation in the hydrophobic (P 1) region</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A new class of chymase inhibitor featuring a benzimidazolone core with an acid side chain and a P
1 hydrophobic moiety is described. Incubation of the lead compound with GSH resulted in the formation of a GSH conjugate on the benzothiophene P
1 moiety. Replacement of the benzothiophene with different heterocyclic systems such as indoles and benzoisothiazole is feasible. Among the P
1 replacements, benzoisothiazole prevents the formation of GSH conjugate and an in silico analysis of oxidative potentials agreed with the experimental outcome.</description><subject>Analytical, structural and metabolic biochemistry</subject><subject>Benzimidazoles - chemistry</subject><subject>Benzimidazoles - metabolism</subject><subject>Benzimidazoles - pharmacology</subject><subject>Benzoisothiazole</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Cathepsin</subject><subject>Chymase</subject><subject>Chymases - antagonists & inhibitors</subject><subject>Chymases - metabolism</subject><subject>Crystallography, X-Ray</subject><subject>Enzymes and enzyme inhibitors</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>GSH</subject><subject>Humans</subject><subject>Hydrolases</subject><subject>Hydrophobic and Hydrophilic Interactions</subject><subject>Indole</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Oxidation-Reduction</subject><subject>Pharmacology. Drug treatments</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Protein Structure, Tertiary</subject><subject>Serine protease</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkT2P1DAQhiME4vYO_gAFcoM4iixjx4kdRAMnvqRDUIBEZzn2mHiVxIvtPbH36_FqF-igmmKed2Y0T1U9orCmQLvnm_Uwm2nNgNI1tGvKujvVivKO1w2H9m61gr6DWvb821l1ntIGgHLg_H51xqhomq6HVfXzNS63fvZW34YpLEh0ItuQccnEjPtZJyR-Gf3gc4gvyMdgd5POPiwkOBJRm-xvkMyY9RAmn5G4EOcj4BeSRyTj3sawHcPgDbn8TOizEvte-g-qe05PCR-e6kX19e2bL1fv6-tP7z5cvbquDaci1y1jg9BIhRDSAgXpwGGruXFcC0CqnaTWWnCsdbLjzBkpkEvR90w7q1lzUT09zt3G8GOHKavZJ4PTpBcMu6SkbKB8q-v-TwoJrAcmCsmOpIkhpYhObaOfddwrCuqgRm3UQY06qFHQqqKmhB6fxu-GGe2fyG8XBXhyAnQyenJRL8anvxxvRNnfF-7lkcPythuPUSXjcTFofUSTlQ3-X3f8As47rfE</recordid><startdate>20110801</startdate><enddate>20110801</enddate><creator>Lo, Ho Yin</creator><creator>Nemoto, Peter A.</creator><creator>Kim, Jin Mi</creator><creator>Hao, Ming-Hong</creator><creator>Qian, Kevin C.</creator><creator>Farrow, Neil A.</creator><creator>Albaugh, Daniel R.</creator><creator>Fowler, Danielle M.</creator><creator>Schneiderman, Richard D.</creator><creator>Michael August, E.</creator><creator>Martin, Leslie</creator><creator>Hill-Drzewi, Melissa</creator><creator>Pullen, Steven S.</creator><creator>Takahashi, Hidenori</creator><creator>De Lombaert, Stéphane</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>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20110801</creationdate><title>Benzimidazolone as potent chymase inhibitor: Modulation of reactive metabolite formation in the hydrophobic (P 1) region</title><author>Lo, Ho Yin ; Nemoto, Peter A. ; Kim, Jin Mi ; Hao, Ming-Hong ; Qian, Kevin C. ; Farrow, Neil A. ; Albaugh, Daniel R. ; Fowler, Danielle M. ; Schneiderman, Richard D. ; Michael August, E. ; Martin, Leslie ; Hill-Drzewi, Melissa ; Pullen, Steven S. ; Takahashi, Hidenori ; De Lombaert, Stéphane</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-522b7ae17778d0108f0fe5a4cf4a70e1af81ddd0f25f8642fc87e487992afda23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Analytical, structural and metabolic biochemistry</topic><topic>Benzimidazoles - chemistry</topic><topic>Benzimidazoles - metabolism</topic><topic>Benzimidazoles - pharmacology</topic><topic>Benzoisothiazole</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Cathepsin</topic><topic>Chymase</topic><topic>Chymases - antagonists & inhibitors</topic><topic>Chymases - metabolism</topic><topic>Crystallography, X-Ray</topic><topic>Enzymes and enzyme inhibitors</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>GSH</topic><topic>Humans</topic><topic>Hydrolases</topic><topic>Hydrophobic and Hydrophilic Interactions</topic><topic>Indole</topic><topic>Medical sciences</topic><topic>Miscellaneous</topic><topic>Oxidation-Reduction</topic><topic>Pharmacology. Drug treatments</topic><topic>Protease Inhibitors - chemical synthesis</topic><topic>Protease Inhibitors - chemistry</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Protein Structure, Tertiary</topic><topic>Serine protease</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lo, Ho Yin</creatorcontrib><creatorcontrib>Nemoto, Peter A.</creatorcontrib><creatorcontrib>Kim, Jin Mi</creatorcontrib><creatorcontrib>Hao, Ming-Hong</creatorcontrib><creatorcontrib>Qian, Kevin C.</creatorcontrib><creatorcontrib>Farrow, Neil A.</creatorcontrib><creatorcontrib>Albaugh, Daniel R.</creatorcontrib><creatorcontrib>Fowler, Danielle M.</creatorcontrib><creatorcontrib>Schneiderman, Richard D.</creatorcontrib><creatorcontrib>Michael August, E.</creatorcontrib><creatorcontrib>Martin, Leslie</creatorcontrib><creatorcontrib>Hill-Drzewi, Melissa</creatorcontrib><creatorcontrib>Pullen, Steven S.</creatorcontrib><creatorcontrib>Takahashi, Hidenori</creatorcontrib><creatorcontrib>De Lombaert, Stéphane</creatorcontrib><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>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</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>Lo, Ho Yin</au><au>Nemoto, Peter A.</au><au>Kim, Jin Mi</au><au>Hao, Ming-Hong</au><au>Qian, Kevin C.</au><au>Farrow, Neil A.</au><au>Albaugh, Daniel R.</au><au>Fowler, Danielle M.</au><au>Schneiderman, Richard D.</au><au>Michael August, E.</au><au>Martin, Leslie</au><au>Hill-Drzewi, Melissa</au><au>Pullen, Steven S.</au><au>Takahashi, Hidenori</au><au>De Lombaert, Stéphane</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Benzimidazolone as potent chymase inhibitor: Modulation of reactive metabolite formation in the hydrophobic (P 1) region</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2011-08-01</date><risdate>2011</risdate><volume>21</volume><issue>15</issue><spage>4533</spage><epage>4539</epage><pages>4533-4539</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A new class of chymase inhibitor featuring a benzimidazolone core with an acid side chain and a P
1 hydrophobic moiety is described. Incubation of the lead compound with GSH resulted in the formation of a GSH conjugate on the benzothiophene P
1 moiety. Replacement of the benzothiophene with different heterocyclic systems such as indoles and benzoisothiazole is feasible. Among the P
1 replacements, benzoisothiazole prevents the formation of GSH conjugate and an in silico analysis of oxidative potentials agreed with the experimental outcome.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>21733690</pmid><doi>10.1016/j.bmcl.2011.05.126</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2011-08, Vol.21 (15), p.4533-4539 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Analytical, structural and metabolic biochemistry Benzimidazoles - chemistry Benzimidazoles - metabolism Benzimidazoles - pharmacology Benzoisothiazole Binding Sites Biological and medical sciences Cathepsin Chymase Chymases - antagonists & inhibitors Chymases - metabolism Crystallography, X-Ray Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology GSH Humans Hydrolases Hydrophobic and Hydrophilic Interactions Indole Medical sciences Miscellaneous Oxidation-Reduction Pharmacology. Drug treatments Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Protein Structure, Tertiary Serine protease Structure-Activity Relationship |
| title | Benzimidazolone as potent chymase inhibitor: Modulation of reactive metabolite formation in the hydrophobic (P 1) region |
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