Journal of medicinal chemistry

Synthesis and biological evaluation of a monocyclic, fully functional analogue of compactin.

PMID 2909732


Compound 8, a monocyclic analogue of compactin, has been prepared and its efficacy as an inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGR) evaluated. The synthesis (Schemes I and II) requires seven steps starting with di-(-)-menthyl fumarate and employs the useful RR-phosphonate reagent 14 to attach the mevinic acid side chain to aldehyde 13. A molecular mechanics study shows that the preferred conformations of 18 (a model for compactin) and 19 (a model for 8) are nearly identical. Compound 8 inhibits HMGR with IC50 = 320 microM, compared to a corresponding value of 32 nM for the compactin ketone, 5. The factor of 10,000 difference in the two inhibitors corresponds to a difference in binding energy of 5.45 kcal mol-1, or 1.36 kcal mol-1 for each of the four carbons of 5 that are missing in analogue 8. This quantitative difference is consistent with the idea that the decalin moiety of the mevinic acids play a purely hydrophobic role in binding the inhibitors to the enzyme.