Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran 2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus
A series of trans-tetrahydro-4-hydroxy-6-[2-(2,3,4,5-substituted-1H-pyrrol-1-yl) ethyl]-2H-pyran-2-ones and their dihydroxy acids were prepared and tested for their ability to inhibit the enzyme HMG-CoA reductase in vitro. Inhibitory potency was found to increase substantially when substituents were...
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| Veröffentlicht in: | Journal of medicinal chemistry 1991-01, Vol.34 (1), p.357-366 |
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| container_issue | 1 |
| container_start_page | 357 |
| container_title | Journal of medicinal chemistry |
| container_volume | 34 |
| creator | Roth, Bruce D Blankley, C. J Chucholowski, A. W Ferguson, E Hoefle, M. L Ortwine, D. F Newton, R. S Sekerke, C. S Sliskovic, D. R Wilson, M |
| description | A series of trans-tetrahydro-4-hydroxy-6-[2-(2,3,4,5-substituted-1H-pyrrol-1-yl) ethyl]-2H-pyran-2-ones and their dihydroxy acids were prepared and tested for their ability to inhibit the enzyme HMG-CoA reductase in vitro. Inhibitory potency was found to increase substantially when substituents were introduced into positions three and four of the pyrrole ring. A systematic exploration of structure-activity relationships at these two positions led to the identification of a compound ((+)-33,(+)-(4R)-trans-2-(4-fluororphenyl)-5-(1-methylethyl)-N,3- diphenyl-1- [(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-4- carboxamide) with five times the inhibitory potency of the fungal metabolite compactin. |
| doi_str_mv | 10.1021/jm00105a056 |
| format | Article |
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A systematic exploration of structure-activity relationships at these two positions led to the identification of a compound ((+)-33,(+)-(4R)-trans-2-(4-fluororphenyl)-5-(1-methylethyl)-N,3- diphenyl-1- [(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-4- carboxamide) with five times the inhibitory potency of the fungal metabolite compactin.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00105a056</identifier><identifier>PMID: 1992137</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Anticholesteremic Agents - chemical synthesis ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Indicators and Reagents ; Liver - enzymology ; Magnetic Resonance Spectroscopy ; Molecular Structure ; Pyrones - chemical synthesis ; Pyrones - chemistry ; Pyrones - pharmacology ; Pyrroles - chemical synthesis ; Pyrroles - chemistry ; Pyrroles - pharmacology ; Rats ; Spectrophotometry, Infrared ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1991-01, Vol.34 (1), p.357-366</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a335t-5d0f6806fe93a6186d9fdf8c7afe310bb4d48dd4a2d49bb41dd05f472a93f9e13</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00105a056$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00105a056$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1992137$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Roth, Bruce D</creatorcontrib><creatorcontrib>Blankley, C. J</creatorcontrib><creatorcontrib>Chucholowski, A. W</creatorcontrib><creatorcontrib>Ferguson, E</creatorcontrib><creatorcontrib>Hoefle, M. L</creatorcontrib><creatorcontrib>Ortwine, D. F</creatorcontrib><creatorcontrib>Newton, R. S</creatorcontrib><creatorcontrib>Sekerke, C. S</creatorcontrib><creatorcontrib>Sliskovic, D. R</creatorcontrib><creatorcontrib>Wilson, M</creatorcontrib><title>Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran 2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of trans-tetrahydro-4-hydroxy-6-[2-(2,3,4,5-substituted-1H-pyrrol-1-yl) ethyl]-2H-pyran-2-ones and their dihydroxy acids were prepared and tested for their ability to inhibit the enzyme HMG-CoA reductase in vitro. Inhibitory potency was found to increase substantially when substituents were introduced into positions three and four of the pyrrole ring. 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Inhibitory potency was found to increase substantially when substituents were introduced into positions three and four of the pyrrole ring. A systematic exploration of structure-activity relationships at these two positions led to the identification of a compound ((+)-33,(+)-(4R)-trans-2-(4-fluororphenyl)-5-(1-methylethyl)-N,3- diphenyl-1- [(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-4- carboxamide) with five times the inhibitory potency of the fungal metabolite compactin.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>1992137</pmid><doi>10.1021/jm00105a056</doi><tpages>10</tpages></addata></record> |
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| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1991-01, Vol.34 (1), p.357-366 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_80435679 |
| source | ACS Publications; MEDLINE |
| subjects | Animals Anticholesteremic Agents - chemical synthesis Hydroxymethylglutaryl-CoA Reductase Inhibitors Indicators and Reagents Liver - enzymology Magnetic Resonance Spectroscopy Molecular Structure Pyrones - chemical synthesis Pyrones - chemistry Pyrones - pharmacology Pyrroles - chemical synthesis Pyrroles - chemistry Pyrroles - pharmacology Rats Spectrophotometry, Infrared Structure-Activity Relationship |
| title | Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran 2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus |
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