Inhibitors of cholesterol biosynthesis. 6. trans-6-[2-(2-N-heteroaryl-3,5-disubstituted- pyrazol-4-yl)ethyl/ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-ones.

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Sliskovic DR, Blankley CJ, Krause BR, Newton RS, Picard JA, Roark WH, Roth BD, Sekerke C, Shaw MK, Stanfield RL

Inhibitors of cholesterol biosynthesis. 6. trans-6-[2-(2-N-heteroaryl-3,5-disubstituted- pyrazol-4-yl)ethyl/ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-ones.

J Med Chem. 1992 May 29;35(11):2095-103.

PubMed ID

1597859 [ View in PubMed

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Abstract

A series of N-heteroaryl-substituted mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and in vivo, and to lower plasma cholesterol in a hypercholesterolemic dog model. The goal of the strategy employed was to design an inhibitor which possessed the pharmacological properties of lovastatin (1), and the physicochemical properties (increased hydrophilicity) of pravastatin (2). Two compounds 20a and 20b, were more potent than lovastatin at inhibiting cholesterol biosynthesis both in vitro and in vivo. In terms of plasma cholesterol lowering, 20a was much more efficacious than lovastatin. In addition to possessing increased biological activity, these compounds are significantly less lipophilic than lovastatin, in fact, 20b has a CLOGP value comparable to pravastatin.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Lovastatin	3-hydroxy-3-methylglutaryl-coenzyme A reductase	IC 50 (nM)	20	N/A	N/A	Details