3bgl
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Hepatoselectivity of Statins: Design and synthesis of 4-sulfamoyl pyrroles as HMG-CoA reductase inhibitors
OverviewOverview
4-Sulfamoyl pyrroles were designed as novel hepatoselective HMG-CoA reductase inhibitors (statins) to reduce myalgia, a statin-induced adverse effect. The compounds were prepared via a [3+2] cycloaddition of a Munchnone with a sulfonamide-substituted alkyne. We identified compounds with greater selectivity for hepatocytes compared to L6-myocytes than rosuvastatin and atorvastatin. There was an inverse correlation of myocyte potencies and ClogP values. A number of analogs were effective at reducing cholesterol in acute and chronic in vivo models but they lacked sufficient chronic in vivo activity to warrant further development.
About this StructureAbout this Structure
3BGL is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Hydroxymethylglutaryl-CoA reductase (NADPH), with EC number 1.1.1.34 Known structural/functional Sites: , , and . Full crystallographic information is available from OCA.
ReferenceReference
Hepatoselectivity of statins: design and synthesis of 4-sulfamoyl pyrroles as HMG-CoA reductase inhibitors., Park WK, Kennedy RM, Larsen SD, Miller S, Roth BD, Song Y, Steinbaugh BA, Sun K, Tait BD, Kowala MC, Trivedi BK, Auerbach B, Askew V, Dillon L, Hanselman JC, Lin Z, Lu GH, Robertson A, Sekerke C, Bioorg Med Chem Lett. 2008 Feb 1;18(3):1151-6. Epub 2007 Dec 5. PMID:18155906
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- Homo sapiens
- Hydroxymethylglutaryl-CoA reductase (NADPH)
- Single protein
- Finzel, B C.
- Park, W K.C.
- Pavlovsky, A.
- RID
- Alternative splicing
- Cholesterol biosynthesis
- Endoplasmic reticulum
- Glycoprotein
- Hmg-coa
- Lipid synthesis
- Membrane
- Nadph
- Oxidoreductase
- Peroxisome
- Polymorphism
- Statin
- Steroid biosynthesis
- Transmembrane