Lipophilic 1,1-bisphosphonates are potent squalene synthase inhibitors and orally active cholesterol lowering agents in vivo.

Ciosek, Carl P.; Magnin, David R.; Harrity, Thomas; Logan, Janette V. H.; Dickson, John K.; Gordon, Eric M.; Hamilton, Kenneth; Jolibois, Kern G.; Kunselman, Lori; Lawrence, R. Michael

doi:10.1016/s0021-9258(19)74540-2

Cited by 99 publications

(42 citation statements)

References 32 publications

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“…Although the concentration of MPEX098 needed for cytoprotection was ten‐fold higher than zaragozic acid, the IC 50 of MPEX098 was 0.41 µM in a squalene synthase cell free assay, whereas the IC 50 of zaragozic acid was 0.012 µM 59 . The IC 50 of MPEX098 is similar to other bisphosphonic inhibitors of squalene synthase 28,60 . The higher concentrations of MPEX098 and zaragozic acid needed to protect cells than implied by the IC 50 values may reflect lower bioavailability or reduced lipophilicity, which prevents transcellular transport across the epithelial barriers 61 .…”

Section: Discussionmentioning

confidence: 91%

“…In the present study, we synthesized nitrogen‐containing bisphosphonates that were designed to inhibit squalene synthase, and screened these compounds for cytoprotection against cholesterol‐dependent cytolysins. Bisphosphonates contain a functional group with a similar structure to diphosphate and can inhibit farnesyl diphosphate synthase or squalene synthase 28 . Bisphosphonic inhibitors of farnesyl diphosphate synthase are widely used for the long‐term treatment of osteoporosis, and have a high safety margin 29 .…”

Section: Discussionmentioning

confidence: 99%

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Bisphosphonate inhibitors of squalene synthase protect cells against cholesterol‐dependent cytolysins

et al. 2021

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Bisphosphonate inhibitors of squalene synthase protect cells against cholesterol‐dependent cytolysins

et al. 2021

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“…So far, several classes of SQS inhibitors have been discovered. SQS substrate analogs suppressed SQS activity (14)(15)(16)(17), and RPR-107393, an SQS inhibitor with quinuclidine, reduced TCHO in marmosets (18). Zaragozic acids or squalestatins were potent inhibitors of SQS in mice, rats, and marmosets (19)(20)(21)(22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the most attention has been paid to inhibitors of squalene synthase (SQS; see refs. [14][15][16][17][18][19][20][21][22][23][24]. Because SQS catalyzes the first step committed to cholesterol and forms squalene by the reductive dimerization of two molecules of farnesyl pyrophosphate (FPP; see ref.…”

mentioning

confidence: 99%

Effect of ER-27856, a novel squalene synthase inhibitor, on plasma cholesterol in rhesus monkeys: comparison with 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors

Hiyoshi

Yanagimachi

Ito

et al. 2000

Journal of Lipid Research

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Squalene synthase (SQS; EC 2.5.1.21) plays an important role in the cholesterol biosynthetic pathway. We discovered ER-28448, 5-{ N -[2-butenyl-3-(2-methoxyphenyl)]-N -methylamino}-1,1-penthylidenebis(phosphonic acid) trisodium salt, as a potent and selective inhibitor of SQS. ER-28448 inhibited SQS in rat liver microsome with an IC 50 value of 3.6 n m . We also prepared ER-27856, the tripivaloyloxymethyl ester prodrug of ER-28448. Although less active than ER-28448 in a liver microsome assay, ER-27856 more potently inhibited cholesterol biosynthesis in rat hepatocytes; and ER-27856 orally inhibited de novo cholesterol biosynthesis in Sprague-Dawley rats, with an ED 50 value of 1.6 mg/kg. In HepG2 cells, ER-27856 upregulated low density lipoprotein receptor activity to 2.1 times that of control. A time-course study indicated that the inhibitory effect of ER-27856 on cholesterol biosynthesis in rats continued for up to 8 h. In a study of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMGRIs), atorvastatin actively suppressed cholesterol biosynthesis for 8 h, whereas the effect of pravastatin and simvastatin diminished at 4 and 8 h, respectively. In rhesus monkeys, 4 days of oral administration of ER-27856 lowered plasma total cholesterol (TCHO) more potently than did these HMGRIs. Whereas atorvastatin significantly elevated plasma alanine aminotransferase, a marker of hepatotoxicity, to 3.7 times at 100 mg/kg, ER-27856 increased the level only 1.4 times at 10 mg/kg, at which doses the hypocholesterolemic effect was equivalent. During 28 days of administration, ER-27856 reduced TCHO and non-high density lipoprotein (non-HDL) cholesterol by 72 and 95%, respectively. These results demonstrate that ER-27856 had more potent hypocholesterolemic activity and less hepatotoxic effect than HMGRIs. ER-27856 may contribute to the treatment of hypercholesterolemic patients. -Hiyoshi, H., M. Yanagimachi, M. Ito, I. Ohtsuka, I. Yoshida, T. Saeki, and H. Tanaka. Effect of ER-27856, a novel squalene synthase inhibitor, on plasma cholesterol in rhesus monkeys: comparison with HMG-CoA reductase inhibitors.

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“…Dolichol is an important cofactor in N-linked glycosylation, which is essential for intracellular membrane-bound receptor processing (Carlberg et al, 1996). Lovastatin has been shown to significantly decrease dolichol and CoQ10 with a subsequent decrease in cholesterol biosynthesis in rats (Ciosek et al, 1993). CoQ10 is a necessary component of the mitochondrial respiratory chain and is therefore essential for ATP production.…”

Section: Inhibition Of Isoprenoid Coenzyme Q10 and Dolichol Biosynthesismentioning

confidence: 99%

Mechanisms of statin‐induced new‐onset diabetes

Paseban

Butler²,

Sahebkar

2019

Journal Cellular Physiology

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Statins, with their lipid‐lowering properties, are a first‐line therapy for the prevention of cardiovascular diseases. Recent evidence, however, suggests that statins can increase the risk of new‐onset diabetes (NOD). The molecular mechanisms of statin‐induced NOD are not precisely known, although some pathophysiologic mechanisms have been suggested. Specific to the beta cell, these mechanisms include alterations in insulin secretion, changes in ion channels, modulation of signaling pathways, and inflammation/oxidative stress. Outwith the beta cell, other suggested mechanisms involve adipocytes, including alterations in adipocyte differentiation and modulation of leptin and adiponectin, and genetic and epigenetic mechanisms, including alterations in microRNA. The evidence supporting these and other mechanisms will be discussed. Greater understanding of the underlying mechanisms linking the onset of diabetes to statin therapy is essential and clinically relevant, as it may enable novel preventative or therapeutic approaches to be instituted and guide the production of a new generation of statins lacking this side effect.

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Lipophilic 1,1-bisphosphonates are potent squalene synthase inhibitors and orally active cholesterol lowering agents in vivo.

Cited by 99 publications

References 32 publications

Bisphosphonate inhibitors of squalene synthase protect cells against cholesterol‐dependent cytolysins

Bisphosphonate inhibitors of squalene synthase protect cells against cholesterol‐dependent cytolysins

Effect of ER-27856, a novel squalene synthase inhibitor, on plasma cholesterol in rhesus monkeys: comparison with 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors

Mechanisms of statin‐induced new‐onset diabetes

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