3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. I. Structural modification of 5-substituted 3,5-dihydroxypentanoic acids and their lactone derivatives

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Abstract
A series of 5-substituted 3,5-dihydroxypentanoic acids and their derivatives were prepared and tested for inhibition of HMG-CoA [3-hydroxy-3-methylglutaryl-coenzyme A] reductase in vitro. In general, unless a carboxylate anion can be formed and the hydroxy groups remain unsubstituted in an erythro relationship, inhibitory activity is greatly reduced. Only one enantiomer of the ring-opened form of (.+-.)-trans-(E)-6-[2-(2,4-dichlorophenyl)ethenyl]-3,4,5,6-tetrahydroxy-2H-pyran-2-one] possesses the activity displayed by the racemate. Insertion of a bridging unit other than ethyl or (E)-ethenyl between the 5-carbinol moiety and an appropriate lipophilic moiety (e.g., 2,4-dichlorophenyl) attenuates activity. [These agents are potential antiatherogenic compounds which act at the level of inhibition of cholesterol synthesis.].

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