Discovery of pyrrolopyridazines as novel DGAT1 inhibitors
A new structural class of DGAT1 inhibitors possessing a pyrrolopyridazine core has been discovered. The optimization of DGAT1 inhibitory activity and increase in selectivity over ACAT1 is described. A new structural class of DGAT1 inhibitors was discovered and the structure–activity relationship was...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010-10, Vol.20 (20), p.6030-6033 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Fox, Brian M. Iio, Kiyosei Li, Kexue Choi, Rebeka Inaba, Takashi Jackson, Simon Sagawa, Shoichi Shan, Bei Tanaka, Masahiro Yoshida, Atsuhito Kayser, Frank |
| description | A new structural class of DGAT1 inhibitors possessing a pyrrolopyridazine core has been discovered. The optimization of DGAT1 inhibitory activity and increase in selectivity over ACAT1 is described.
A new structural class of DGAT1 inhibitors was discovered and the structure–activity relationship was explored. The pyrrolotriazine core of the original lead molecule was changed to a pyrrolopyridazine core providing an increase in potency. Further exploration resulted in optimization of the propyl group at C7 and the discovery that the ester at C6 could be replaced by five-membered heterocyclic rings. The analogs prepared have DGAT1 IC
50 values ranging from >10
μM to 48
nM. |
| doi_str_mv | 10.1016/j.bmcl.2010.08.066 |
| format | Article |
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A new structural class of DGAT1 inhibitors was discovered and the structure–activity relationship was explored. The pyrrolotriazine core of the original lead molecule was changed to a pyrrolopyridazine core providing an increase in potency. Further exploration resulted in optimization of the propyl group at C7 and the discovery that the ester at C6 could be replaced by five-membered heterocyclic rings. The analogs prepared have DGAT1 IC
50 values ranging from >10
μM to 48
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A new structural class of DGAT1 inhibitors was discovered and the structure–activity relationship was explored. The pyrrolotriazine core of the original lead molecule was changed to a pyrrolopyridazine core providing an increase in potency. Further exploration resulted in optimization of the propyl group at C7 and the discovery that the ester at C6 could be replaced by five-membered heterocyclic rings. The analogs prepared have DGAT1 IC
50 values ranging from >10
μM to 48
nM.</description><subject>Acyl CoA:diacylglycerol acyltransferase</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>DGAT1</subject><subject>DGAT1 inhibitors</subject><subject>Diacylglycerol O-Acyltransferase - antagonists & inhibitors</subject><subject>Diacylglycerol O-Acyltransferase - metabolism</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. Drug treatments</subject><subject>Pyridazines - chemical synthesis</subject><subject>Pyridazines - chemistry</subject><subject>Pyridazines - pharmacology</subject><subject>Pyrroles - chemical synthesis</subject><subject>Pyrroles - chemistry</subject><subject>Pyrroles - pharmacology</subject><subject>Pyrrolopyridazines</subject><subject>Sterol O-Acyltransferase - antagonists & inhibitors</subject><subject>Sterol O-Acyltransferase - metabolism</subject><subject>Structure-Activity Relationship</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>eNp9kEtLAzEQx4Motj6-gAfZi3jaOnlsNgteSusLBC8K3kI2D0zZbmrSFuqnN6VVb55mmPnN8OeH0AWGEQbMb2ajdq67EYE8ADECzg_QEDPOSsqgOkRDaDiUomHvA3SS0gwAM2DsGA0ICEqBiiFqpj7psLZxUwRXLDYxhi7k4o368r1NhUpFn_ddMX0Yv-LC9x--9csQ0xk6cqpL9nxfT9Hb_d3r5LF8fnl4moyfS01FtSwNNoYRoQk4JxRjFWmwswQ3inNDBWlrgIrVPDdWV04wykHjltQ1c8ZiTk_R9e7vIobPlU1LOc-Rbdep3oZVkk3FqgYLzDJJdqSOIaVonVxEP1dxIzHIrTE5k1tjcmtMgpDZWD663L9ftXNrfk9-FGXgag-opFXnouq1T38cpYRBTTN3u-NslrH2Nsqkve21NT5avZQm-P9yfAOdZ4gm</recordid><startdate>20101015</startdate><enddate>20101015</enddate><creator>Fox, Brian M.</creator><creator>Iio, Kiyosei</creator><creator>Li, Kexue</creator><creator>Choi, Rebeka</creator><creator>Inaba, Takashi</creator><creator>Jackson, Simon</creator><creator>Sagawa, Shoichi</creator><creator>Shan, Bei</creator><creator>Tanaka, Masahiro</creator><creator>Yoshida, Atsuhito</creator><creator>Kayser, Frank</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20101015</creationdate><title>Discovery of pyrrolopyridazines as novel DGAT1 inhibitors</title><author>Fox, Brian M. ; Iio, Kiyosei ; Li, Kexue ; Choi, Rebeka ; Inaba, Takashi ; Jackson, Simon ; Sagawa, Shoichi ; Shan, Bei ; Tanaka, Masahiro ; Yoshida, Atsuhito ; Kayser, Frank</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c385t-d1dd428c20ff8a445291fe219a66d382b70054762b7ec5f84360c1b2774fde163</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Acyl CoA:diacylglycerol acyltransferase</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>DGAT1</topic><topic>DGAT1 inhibitors</topic><topic>Diacylglycerol O-Acyltransferase - antagonists & inhibitors</topic><topic>Diacylglycerol O-Acyltransferase - metabolism</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>General and cellular metabolism. Vitamins</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyridazines - chemical synthesis</topic><topic>Pyridazines - chemistry</topic><topic>Pyridazines - pharmacology</topic><topic>Pyrroles - chemical synthesis</topic><topic>Pyrroles - chemistry</topic><topic>Pyrroles - pharmacology</topic><topic>Pyrrolopyridazines</topic><topic>Sterol O-Acyltransferase - antagonists & inhibitors</topic><topic>Sterol O-Acyltransferase - metabolism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fox, Brian M.</creatorcontrib><creatorcontrib>Iio, Kiyosei</creatorcontrib><creatorcontrib>Li, Kexue</creatorcontrib><creatorcontrib>Choi, Rebeka</creatorcontrib><creatorcontrib>Inaba, Takashi</creatorcontrib><creatorcontrib>Jackson, Simon</creatorcontrib><creatorcontrib>Sagawa, Shoichi</creatorcontrib><creatorcontrib>Shan, Bei</creatorcontrib><creatorcontrib>Tanaka, Masahiro</creatorcontrib><creatorcontrib>Yoshida, Atsuhito</creatorcontrib><creatorcontrib>Kayser, Frank</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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</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>Fox, Brian M.</au><au>Iio, Kiyosei</au><au>Li, Kexue</au><au>Choi, Rebeka</au><au>Inaba, Takashi</au><au>Jackson, Simon</au><au>Sagawa, Shoichi</au><au>Shan, Bei</au><au>Tanaka, Masahiro</au><au>Yoshida, Atsuhito</au><au>Kayser, Frank</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of pyrrolopyridazines as novel DGAT1 inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2010-10-15</date><risdate>2010</risdate><volume>20</volume><issue>20</issue><spage>6030</spage><epage>6033</epage><pages>6030-6033</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A new structural class of DGAT1 inhibitors possessing a pyrrolopyridazine core has been discovered. The optimization of DGAT1 inhibitory activity and increase in selectivity over ACAT1 is described.
A new structural class of DGAT1 inhibitors was discovered and the structure–activity relationship was explored. The pyrrolotriazine core of the original lead molecule was changed to a pyrrolopyridazine core providing an increase in potency. Further exploration resulted in optimization of the propyl group at C7 and the discovery that the ester at C6 could be replaced by five-membered heterocyclic rings. The analogs prepared have DGAT1 IC
50 values ranging from >10
μM to 48
nM.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>20833038</pmid><doi>10.1016/j.bmcl.2010.08.066</doi><tpages>4</tpages></addata></record> |
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| subjects | Acyl CoA:diacylglycerol acyltransferase Biological and medical sciences Cell Line DGAT1 DGAT1 inhibitors Diacylglycerol O-Acyltransferase - antagonists & inhibitors Diacylglycerol O-Acyltransferase - metabolism Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology General and cellular metabolism. Vitamins Humans Inhibitory Concentration 50 Medical sciences Pharmacology. Drug treatments Pyridazines - chemical synthesis Pyridazines - chemistry Pyridazines - pharmacology Pyrroles - chemical synthesis Pyrroles - chemistry Pyrroles - pharmacology Pyrrolopyridazines Sterol O-Acyltransferase - antagonists & inhibitors Sterol O-Acyltransferase - metabolism Structure-Activity Relationship |
| title | Discovery of pyrrolopyridazines as novel DGAT1 inhibitors |
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