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Squalene synthase inhibitor

Scheme 7.6 Stereoselective acetylation of the hydroxyl diethyl ester (9) to the (S)-acetate as an intermediate for the synthesis of a squalene synthase inhibitor ( ) of cholesterol synthesis. Scheme 7.6 Stereoselective acetylation of the hydroxyl diethyl ester (9) to the (S)-acetate as an intermediate for the synthesis of a squalene synthase inhibitor ( ) of cholesterol synthesis.
Watson NS and Procopiou PA (1996) Squalene synthase inhibitors their potential as hypocholesterolaemic agents. Prog Med Chem 33, 331-378. [Pg.120]

Figure 17 Enzymatic synthesis of chiral synthon for BMS-188494, a squalene synthase inhibitor stereoselective acetylation of racemic (52). Figure 17 Enzymatic synthesis of chiral synthon for BMS-188494, a squalene synthase inhibitor stereoselective acetylation of racemic (52).
C Dufresne, KE Wilson, D Zink, J Smith, JD Bergstrom, M Kurtz, D Rew, M Nallin, R Jenkins. The isolation and structure elucidation of zaragozic acid C, a novel potent squalene synthase inhibitor. Tetrahedron 48 10221-10226, 1992. [Pg.172]

Magnin, D.R., et al. (1995). 1,1-Bisphosphonate squalene synthase inhibitors interplay between the isoprenoid subuntit and the diphophate surrogate. J Med Chem 38 2596-2605. [Pg.122]

The squalestatins represent the first novel class of squalene synthase inhibitors to be isolated from a microbial source. Numerous attempts have been made to synthesise inhibitors chemically, but the most active of these is still 10-fold less potent than the squalestatins. [Pg.83]

Eliminations. Specially designed sulfones undergo elimination which is initiated by a remote radical. The alkyl moiety is converted to an alkene. The core of the squalene synthase inhibitor CP-225917 has been synthesized via a radical cyclization with ejection of an allylic phenylthio group. The radical precursor is an a-bromoacetic ester. [Pg.183]

I, 1-Bisphosphonate squalene synthase inhibitors. Interplay between the isoprenoid subunit and the diphosphate surrogate, J. Med. Chem.. 38, 2596, 1995. [Pg.486]

The squalestatins (also known as zaragozic acids) are a family of potent squalene synthase inhibitors with potential use as anticholesterol compounds. [Pg.36]

CJ-15,183 (44) has been isolated from the fermentation culture of the fungus, Aspergillus aculeatus CL38916 as a squalene synthase inhibitor. The compound potently inhibited rat liver and human squalene synthases. In addition, it showed antifungal activities against filamentous fungi and yeast. The structure was elucidated to be an aliphatic tetracarboxylic acid compound consisting of an alkyl y-lactone, malic acid and isocitric acid moieties by spectroscopic analyses [69]. [Pg.773]

CJ-13,981 (45) and CJ-13,982 (46) were isolated from the fermentation broth of CL 15036, an unidentified fungus, as new squalene synthase inhibitors. They inhibited human liver microsomal squalene synthase with IC50 values of 2.8 and 1.1 pM, respectively. Based on the spectroscopic analyses, the structures of CJ-13,981 and CJ-13,982 were elucidated to be highly carboxylated fatty acids, 3-hydroxy-3,4-dicarboxy-15-hexadecenoic acid (45) and 3-hydroxy-3,4-dicarboxyhexa-decanoic acid (46), respectively [70]. [Pg.774]

Recently, a Streptomyces species microorganism that produces squalene synthase inhibitors was screened from soils, and two active inhibitors were isolated from its culture broth. Structures of these inhibitors were identified as macrolactins A (47) and F (48) on the basis of spectral analyses. The IC50 values for macrolactin A were 0.11, 1.66, and 1.08 pM for the squalene synthases of pig liver, rat liver and Hep G2 cells, respectively. Macrolactin F also showed significant inhibitory activities with IC50 values of 0.14, 1.53, and 0.99 pM, respectively. Kinetic results for macrolactins A and F showed that they appear to be... [Pg.774]

On the other hand, HMG-CoA reductase inhibitors have also been shown to decrease the biosynthesis of other biologically important isoprenoid compounds derived from mevalonate. Thus, there has been continued interest in developing hypolipidemic agents that inhibit the enzymes involved specifically in the later stages of cholesterol biosynthesis. Zaragozic acid derivatives were isolated from several microbial species and they exhibited dose-dependent inhibition of cholesterol biosynthesis as potent squalene synthase inhibitors. Viridiofungins, bisabosquals, macrolactins, CJ-15,183, CJ-13,981 and CJ-13,982 were also isolated as mammalian squalene synthase inhibitors of microbial origin. [Pg.780]

Squalene synthase is an enzyme catalyzing the formation of squalene from farnesyl diphosphate which is a committed step in the cholesterol biosynthetic pathway. Therefore, squalene synthase is considered a better target than HMG-CoA reductase because farnesyl pyrophosphate, a downstream product of HMG-CoA reductase, is needed for prenylation of proteins and for the biosyntheses of ubiquinone and dolichol (Fig. 2). Before squalestatins and zaragozic acids were discovered, a number of squalene synthase inhibitors were synthesized that showed respectable inhibitory potencies in vitro, but none were successful in animal testing [41]. It was the discovery of squalestatins and zaragozic acids that renewed interest in this biological target, and at picomolar potencies they were the most active inhibitors of squalene synthase. [Pg.253]

F. (1993) The zaragozic acids structure elucidation of a new class of squalene synthase inhibitors. Tet Lett. 34, 399-402. [Pg.328]

Chan C, Andreotti D, Cox B, et al. The squalestatins decarboxy and 4-deoxy analogues as potent squalene synthase inhibitors. J Med Chem 1996 39 207-216. [Pg.1206]

Potent squalene synthase inhibitors were simultaneously discovered and named squalestatins and zaragozic acids by Glaxo-Wellcome and Merck and Co., respectively. These series of compounds contain an alkyl bicyclic core with three free carboxyl groups and an acyl side chain and are representative of the class (Figure 17). [Pg.431]

Carotenoids, Retenoids, Pheromones and Polyenes.-A convenient route to exclusively ( )-allylic phosphonates (e.g. 165), compounds which are useful in polyene synthesis, is provided by the base-catalysed isomerisation of the corresponding vinylphosphonates. " The bis(trifluoromethyl) analogue (167) of a known, potent squalene synthase inhibitor has been synthesised using the Wittig reaction of (166) with hexafluoroacetone as a key step. ... [Pg.286]

A whole series of other development compounds have shared the same fate. For example, lapaquistat this first squalene synthase inhibitor in Phase 111 din-ical trials was abandoned by Takeda in 2008 due to liver toxicity, which occurred even at low doses (Fig. 5.160). [408]... [Pg.437]

Lan S, Hsieh DC, Hillyer JW, Fancher RM, Rinehart KJ, Warrack BM, White RE (1998) Metabolism of a-phosphonosulfonate squalene synthase inhibitors. I. Disposition of a famesylethyl a-phosphonosulfonate and ester prodrugs in rats. Drug Metab Dispos 26 993-1000... [Pg.149]

Dickson JK, Biller SA, Magnin DR, Petrillo EW, Hillyer JW, Hsieh DC, Lan SJ, Rinehart JK, Gregg RE, Harrity TW et al (1996) Orally active squalene synthase inhibitors bis((acyloxy) alkyl) prodrags of the alpha-phosphonosulfonic acid moiety. J Med Chem 39 661-664... [Pg.155]


See other pages where Squalene synthase inhibitor is mentioned: [Pg.923]    [Pg.184]    [Pg.192]    [Pg.148]    [Pg.149]    [Pg.173]    [Pg.160]    [Pg.923]    [Pg.381]    [Pg.590]    [Pg.101]    [Pg.207]    [Pg.764]    [Pg.765]    [Pg.253]    [Pg.160]    [Pg.1243]    [Pg.121]    [Pg.135]    [Pg.143]    [Pg.159]   
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See also in sourсe #XX -- [ Pg.381 ]

See also in sourсe #XX -- [ Pg.764 ]

See also in sourсe #XX -- [ Pg.797 ]




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