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

Stokker, G. E.; Hoffman, William F.; Alberts, Alfred W.; Cragoe, Edward J.; Deana, A. A.; Gilfillan, J. L.; Huff, Jesse W.; Novello, F.; Prugh, John D.

doi:10.1021/jm00381a014

Cited by 107 publications

(29 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…4, 14. 15]: lovastatin [16], pravastatin [17], simvastatin [18], and fluvastatin [19], A number of clinical studies have demonstrated that HMG-CoA re ductase inhibitors (statins), either alone or in association with other hypolipidemic drugs, can induce regression of vascular atherosclerosis [9][10][11]. decrease the incidence of coronary artery disease [9,10], and improve survival in patients with coronary artery disease [8],…”

Section: Introductionmentioning

confidence: 99%

Non-Lipid-Related Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors

Corsini¹,

Bernini²,

Quarato³

et al. 1996

Cardiology

View full text Add to dashboard Cite

With the increasing knowledge of the pathogenesis of atherosclerosis, it appears that in the future the prevention of cardiovascular disease will involve not only risk factor correction, but also direct pharmacological control of processes occurring in the arterial wall. Among these, a pivotal role is played by smooth muscle cell (SMC) migration and proliferation, which, together with lipid deposition, are prominent features of atherogenesis and restenosis after angioplasty. Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are essential for cell growth, hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently, we provided in vitro and in vivo evidence that fluvastatin, simvastatin and lovastatin, but not pravastatin, decrease SMC migration and proliferation dose dependently, independently of their hypocholesterolemic properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70-90% decrease) was prevented completely by the addition of mevalonate, and partially prevented by farnesol and geranylgeraniol (80%), confirming the specific role of isoprenoid metabolites in regulating these cellular events, probably through prenylated protein(s). The in vivo antiproliferative activity of fluvastatin on neointimal hyperplasia in normocholesterolemic rabbits was also prevented fully by the local delivery of mevalonate, by means of an Alzet pump. Fluvastatin and simvastatin also inhibited cholesterol esterification and deposition induced by acetylated LDL in cultured macrophages. This effect was fully prevented by the addition of mevalonate or geranylgeraniol. Taken together, these results suggest that, beyond their effects on plasma lip-ids, HMG-CoA reductase inhibitors exert a direct antiatherosclerotic effect on the arterial wall, probably through local inhibition of isoprenoid biosynthesis.

show abstract

Section: Introductionmentioning

confidence: 99%

Non-Lipid-Related Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors

Corsini¹,

Bernini²,

Quarato³

et al. 1996

Cardiology

View full text Add to dashboard Cite

show abstract

“…From the structural prospective, these natural and semisynthetic statins are chiral 3,5-dihydroxyheptanoic acids that bind at C-7 to the substituted chiral unsaturated decalin core. The 3,5-dihydroxyheptanoic acid structural motif has been shown to be responsible for the pharmacological activity of statins [8].…”

Section: Discovery Of Statinsmentioning

confidence: 99%

Recent Progress in the Synthesis of Super-Statins

Časar

2015

Topics in Heterocyclic Chemistry

View full text Add to dashboard Cite

Super-statins now represent a mature class of marketed drugs that faces the patent cliff, as has already occurred for fluvastatin and atorvastatin and is approaching for rosuvastatin and pitavastatin. However, they continue to trigger huge scientific interest in terms of their efficient preparation. This is not surprising, as easier accessibility of super-statins will promote even bigger demand in the market and consequently the need for higher rates of the production and productivity. Therefore, the stimulus for the development of even more efficient synthetic approaches to the heterocyclic moieties of super-statins and their chiral lateralchain precursors is at a peak, as also for the assembly of the these two parts into super-statins. The present report summarizes recent developments in the field of the synthesis of super-statins published from 2010 to 2015. Emphasis is given to the analysis of novel approaches to the formation of the chiral statin lateral chain, with detailed discussion of the development of new routes to respective heterocyclic cores and the assembly of these key units into the final super-statin structure.

show abstract

“…The insertion of a bridging unit other than ethyl or an (E)-ethenyl between the 5-carbinol moiety and an appropriate lipophilic moiety attenuates the activity. Other derivatives which have different inhibition activities help to determine the essentiality of the functional group [47]. Fig.…”

Section: Fig (2b)mentioning

confidence: 99%

“…3A) shows better inhibition activity (IC 50 = 22 M) of HMG-CoA reductase among a series of 5-substituted 3,5-dihydroxypentanoic acids and their derivatives in in vitro condition. It has been reported that the insertion of a bridging unit other than ethyl or (E)-ethenyl between 2,4-dichlorophenyl and 5-carbinol moiety had decreased the activity [47].…”

Section: Origin and Routes Of Synthesis Of Hypo-cholesterolemic Compomentioning

confidence: 99%

Characterization, Modes of Synthesis, and Pleiotropic Effects of Hypocholesterolemic Compounds - A Review

Seenivasan¹,

Panda

Théodore³

2011

TOEIJ

View full text Add to dashboard Cite

Studies on the various cholesterol-lowering agents is one of the important areas in clinical research. Identification and characterization of potential molecules from various sources have been carried out in the past and their relationship with the enzymes which are involved in the cholesterol cascade is gaining interest. In this review, we have highlighted various inhibitors involved in the cholesterol cascade as well as cholesterol-lowering agents, viz., tocotrienol, flavonoids, phytosterols, phytostanols, statins, DADS, and synthetic compounds. The mechanism of action and characterization of these hypocholesterolemic compounds are discussed in this communication. Major natural sources as well as synthetic and biological routes of synthesis of these compounds are reviewed in a concise manner. Especially, various HMG-CoA analogues including statins have been reviewed specifically.

show abstract

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

Cited by 107 publications

References 2 publications

Non-Lipid-Related Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors

Non-Lipid-Related Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors

Recent Progress in the Synthesis of Super-Statins

Characterization, Modes of Synthesis, and Pleiotropic Effects of Hypocholesterolemic Compounds - A Review

Contact Info

Product

Resources

About