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

• Published in: Journal of medicinal chemistry 1990-01, Vol.33 (1), p.21-31
• Main Authors: Roth, Bruce D, Ortwine, D. F, Hoefle, M. L, Stratton, C. D, Sliskovic, D. R, Wilson, M. W, Newton, R. S
• Format: Article
• Language: English
• Subjects: Animals; Chemical Phenomena; Chemistry; Chemistry, Physical; Cholesterol - biosynthesis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lactones; Liver - enzymology; Lovastatin - analogs & derivatives; Lovastatin - pharmacology; Molecular Conformation; Molecular Structure; Pyrans - chemical synthesis; Pyrans - pharmacology; Pyrroles - chemical synthesis; Pyrroles - pharmacology; Rats; Structure-Activity Relationship; trans-6-(2-pyrrol-1-ylethyl)-4-hydroxypyran-2-ones
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00163a005

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, which possessed 30% 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 A for the 2- and 5-substituents, respectively, as well as an overall width limit of 10.6 A 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, theta = 80-110 degrees). 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 with equal or slightly reduced potencies when compared to the 2-[(unsubstituted or 4-fluoro)phenyl]pyrroles, supporting the hypothesis that inhibitory potency is relatively insensitive to side-chain polarity or charge distribution in this area.