Discovery of [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b] pyridin-1-yl]acetic acids as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications
Efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acid aldose reductase inhibitors. The lead candidate, [6-methyl-3-(4,5,7-tr...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2009-04, Vol.19 (7), p.2006-2008 |
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| container_end_page | 2008 |
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| container_issue | 7 |
| container_start_page | 2006 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 19 |
| creator | VAN ZANDT, Michael C DOAN, Brian SAWICKI, Diane R SREDY, Janet PODJARNY, Alberto D |
| description | Efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acid aldose reductase inhibitors. The lead candidate, [6-methyl-3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acid example 16, inhibits aldose reductase with an IC50 of 8 nM, while being inactive against aldehyde reductase (IC50>100 microM), a related enzyme involved in the detoxification of reactive aldehydes. |
| doi_str_mv | 10.1016/j.bmcl.2009.02.037 |
| format | Article |
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The lead candidate, [6-methyl-3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acid example 16, inhibits aldose reductase with an IC50 of 8 nM, while being inactive against aldehyde reductase (IC50>100 microM), a related enzyme involved in the detoxification of reactive aldehydes.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2009.02.037</identifier><identifier>PMID: 19250825</identifier><language>eng</language><publisher>Amsterdam: Elsevier</publisher><subject>Acetates - chemical synthesis ; Acetates - chemistry ; Acetates - pharmacology ; Aldehyde Reductase - antagonists & inhibitors ; Aldehyde Reductase - metabolism ; Benzothiazoles - chemical synthesis ; Benzothiazoles - chemistry ; Benzothiazoles - pharmacology ; Biological and medical sciences ; Catalytic Domain ; Chronic Disease ; Computer Simulation ; Crystallography, X-Ray ; Diabetes Complications - drug therapy ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; General and cellular metabolism. 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The lead candidate, [6-methyl-3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acid example 16, inhibits aldose reductase with an IC50 of 8 nM, while being inactive against aldehyde reductase (IC50>100 microM), a related enzyme involved in the detoxification of reactive aldehydes.</description><subject>Acetates - chemical synthesis</subject><subject>Acetates - chemistry</subject><subject>Acetates - pharmacology</subject><subject>Aldehyde Reductase - antagonists & inhibitors</subject><subject>Aldehyde Reductase - metabolism</subject><subject>Benzothiazoles - chemical synthesis</subject><subject>Benzothiazoles - chemistry</subject><subject>Benzothiazoles - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Catalytic Domain</subject><subject>Chronic Disease</subject><subject>Computer Simulation</subject><subject>Crystallography, X-Ray</subject><subject>Diabetes Complications - drug therapy</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>General and cellular metabolism. Vitamins</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Medical sciences</subject><subject>Pharmacology. 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Vitamins</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>VAN ZANDT, Michael C</creatorcontrib><creatorcontrib>DOAN, Brian</creatorcontrib><creatorcontrib>SAWICKI, Diane R</creatorcontrib><creatorcontrib>SREDY, Janet</creatorcontrib><creatorcontrib>PODJARNY, Alberto D</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>Hyper Article en Ligne (HAL)</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>VAN ZANDT, Michael C</au><au>DOAN, Brian</au><au>SAWICKI, Diane R</au><au>SREDY, Janet</au><au>PODJARNY, Alberto D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b] pyridin-1-yl]acetic acids as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2009-04-01</date><risdate>2009</risdate><volume>19</volume><issue>7</issue><spage>2006</spage><epage>2008</epage><pages>2006-2008</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acid aldose reductase inhibitors. The lead candidate, [6-methyl-3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acid example 16, inhibits aldose reductase with an IC50 of 8 nM, while being inactive against aldehyde reductase (IC50>100 microM), a related enzyme involved in the detoxification of reactive aldehydes.</abstract><cop>Amsterdam</cop><pub>Elsevier</pub><pmid>19250825</pmid><doi>10.1016/j.bmcl.2009.02.037</doi><tpages>3</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2009-04, Vol.19 (7), p.2006-2008 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Acetates - chemical synthesis Acetates - chemistry Acetates - pharmacology Aldehyde Reductase - antagonists & inhibitors Aldehyde Reductase - metabolism Benzothiazoles - chemical synthesis Benzothiazoles - chemistry Benzothiazoles - pharmacology Biological and medical sciences Catalytic Domain Chronic Disease Computer Simulation Crystallography, X-Ray Diabetes Complications - drug therapy Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology General and cellular metabolism. Vitamins Humans Inhibitory Concentration 50 Medical sciences Pharmacology. Drug treatments |
| title | Discovery of [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b] pyridin-1-yl]acetic acids as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications |
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