2r4f

Substituted Pyrazoles as Hepatselective HMG-COA reductase inhibitors

spinqualitylabelsall models 2r4f, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2r4f is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: RIE, SO4 Related: 2q1l, 2q6b, 2q6c, 3bgl Gene: HMGCR (HUMAN) Activity: Hydroxymethylglutaryl-CoA reductase (NADPH), with EC number 1.1.1.34 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [HMDH_HUMAN] Transmembrane glycoprotein that is the rate-limiting enzyme in cholesterol biosynthesis as well as in the biosynthesis of nonsterol isoprenoids that are essential for normal cell function including ubiquinone and geranylgeranyl proteins. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed In light of accumulating evidence that aggressive LDL-lowering therapy may offer increased protection against coronary heart disease, we undertook the design and synthesis of a novel series of HMG-CoA reductase inhibitors based upon a substituted pyrazole template. Optimizing this series using both structure-based design and molecular property considerations afforded a class of highly efficacious and hepatoselective inhibitors resulting in the identification of (3 R,5 R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2 H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic (PF-3052334) as a candidate for the treatment of hypercholesterolemia. Substituted pyrazoles as hepatoselective HMG-CoA reductase inhibitors: discovery of (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H -pyrazol-3-yl]-3,5-dihydroxyheptanoic acid (PF-3052334) as a candidate for the treatment of hypercholesterolemia.,Pfefferkorn JA, Choi C, Larsen SD, Auerbach B, Hutchings R, Park W, Askew V, Dillon L, Hanselman JC, Lin Z, Lu GH, Robertson A, Sekerke C, Harris MS, Pavlovsky A, Bainbridge G, Caspers N, Kowala M, Tait BD J Med Chem. 2008 Jan 10;51(1):31-45. Epub 2007 Dec 12. PMID:18072721 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also HMG-CoA Reductase 3D structures

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