123184-25-8Relevant articles and documents
Inhibitors of Cholesterol Biosynthesis. 1. trans-6-(2-Pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a Novel Series of HMG-CoA Reductase Inhibitors. 1. Effects of Structural Modifications at the 2- and 5-Positions of the Pyrrole Nucleus
Roth, B. D.,Ortwine, D. F.,Hoefle, M. L.,Stratton, C. D.,Sliskovic, D. R.,et al.
, p. 21 - 31 (2007/10/02)
A novel series of trans-6-(2-pyrrol-1-ylethyl)-4-hydroxypyran-2-ones and their dihydroxy acid derivatives were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase in vitro.A systematic study of substitution at the 2- and 5-positions of the pyrrole ring revealed that optimum potency was realized with the 2-(4-fluorophenyl)-5-isopropyl derivative 8x (Table III), which possessed 30percent of the in vitro activity of the potent fungal metabolite compactin (I).A molecular modeling analysis led to the description of a pharmacophore model characterized by (A) length limits of 5.9 and 3.3 Angstroem for the 2- and 5-substituents, respectively, as well as an overall width limit of 10.6 Angstroem across the pyrrole ring from the 2- to the 5-substituent and (B) an orientation of the ethyl(ene) bridge to the 4-hydroxypyran-2-one ring nearly perpendicular to the planes of the parent pyrrole, hexahydronaphthalene, and phenyl rings of the structures examined (Figure 3, θ = 80-110 deg).Attempts to more closely mimic compactin's polar isobutyric ester side chain with the synthesis of 2-phenylpyrroles containing polar phenyl substituents resulted in analogues (Table III, 8m-p) with equal or slightly reduced potencies when compared to the 2-pyrroles, supporting the hypothesis that inhibitory potency is relatively insensitive to side-chain polarity or charge distribution in this area.
