- HMG-COA REDUCTASE DEGRADATION INDUCING COMPOUND
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The present invention relates HMG-CoA reductase degradation inducing compounds. Specifically, the present invention relates a bifunctional compound in which a HMG-CoA reductase binding moiety and an E3 ubiquitin ligase-binding moiety are linked by a chemical linker. The present invention also relates a method for preparing the compounds, and a method for degradation of HMG-CoA reducatase using the compounds, as well as use for prevention or treatment of HMG-CoA reductase related diseases using the compounds.
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Paragraph 463-466
(2021/10/11)
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- A compound targeting ubiquitination degradation HMGCR or a pharmaceutically acceptable salt thereof. Preparation method and application
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The invention relates to a compound of targeted ubiquitination degradation HMGCR or a pharmaceutically acceptable salt thereof as well as a preparation method and application thereof. The structure is shown in the general formula (I). The compound or the
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Paragraph 0058-0061
(2021/10/27)
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- Hydroxy methyl glutaryl coenzyme A reductase inhibitors
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The invention relates to a compound, in particular to an HMG-GoA reductase inhibitor. The HMG-GoA reductase inhibitor is ester formed by naphthol and Cn polyhydroxyalkanoate or Cn olefine acid of the compound in the formula I, wherein n is an integer from six to fourteen. The compound can be effectively used for treating or preventing dyslipidemia, for example, the compound can effectively treat or prevent hypercholesteremia or mixed type hyperlipidemia.
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Paragraph 0074; 0075; 0076
(2017/04/29)
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- Synthesis and biological evaluation of lovastatin-derived aliphatic hydroxamates that induce reactive oxygen species
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Some hydroxamate compounds induce cancer cell death by intracellular reactive oxygen species (ROS). This study introduced the hydroxamate core into lovastatin, a fungus metabolite clinically used for the treatment of hypercholesterolemia. The resulting co
- Lin, Ruo-Kai,Lin, Yuh-Feng,Hsu, Ming-Jen,Hsieh, Chang-Lin,Wang, Chen-Yu,Huang, Chih-Chiang,Huang, Wei-Jan
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supporting information
p. 5528 - 5533
(2016/11/09)
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- DUAL ACTION INHIBITORS AGAINST HISTONE DEACETYLASES AND 3-HYDROXY-3-METHYLGLUTARYL COENZYME A REDUCTASE
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Disclosed herein are novel compounds of formula (I), and uses thereof. The compounds of Formula (I) are inhibitors of histone deacetylases (HDACs) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR). Also provided are methods of using the
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- Design and synthesis of dual-action inhibitors targeting histone deacetylases and 3-hydroxy-3-methylglutaryl coenzyme a reductase for cancer treatment
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A series of dual-action compounds were designed to target histone deacetylase (HDAC) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) by having a hydroxamate group essential for chelation with the zinc ion in the active site of HDAC and the key structural elements of statin for binding with both proteins. In our study, the statin hydroxamic acids prepared by a fused strategy are most promising in cancer treatments. These compounds showed potent inhibitory activities against HDACs and HMGR with IC50 values in the nanomolar range. These compounds also effectively reduced the HMGR activity as well as promoted the acetylations of histone and tubulin in cancer cells, but were not toxic to normal cells.
- Chen, Jhih-Bin,Chern, Ting-Rong,Wei, Tzu-Tang,Chen, Ching-Chow,Lin, Jung-Hsin,Fang, Jim-Min
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p. 3645 - 3655
(2013/06/27)
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- HYPOCHOLESTEROLEMIC, ANTI-INFLAMMATORY AND ANTIEPILEPTIC NEUROPROTECTIVE COMPOUND
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The present invention describes a compound of formula (I) its hydroxy acid form, the pharmaceutically acceptable salts of said hydroxy acid and pharmaceutically acceptable prodrugs and solvates of the compound and of its hydroxy acid form and, in particular, said compound, its hydroxy acid form, salts, etc. for use in the prevention of: neurodegenerative diseases, cognitive impairment, diseases associated with undesired oxidation, age-associated pathological processes and progeria, cardiovascular diseases such as atherosclerosis, atrial fibrillation, dyslipidemia, hypercholesterolemia, hyperlipidemia, and hypertriglyceridemia, inflammation or inflammatory processes, or epilepsy, epileptic seizures and convulsions.
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Paragraph 0102; 0103;
(2013/08/14)
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- HYPOCHOLESTEROLEMIC, ANTI-INFLAMMATORY AND ANTIEPILEPTIC NEUROPROTECTIVE COMPOUND
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The present invention describes a compound of formula (I) its hydroxy acid form, the pharmaceutically acceptable salts of said hydroxy acid and pharmaceutically acceptable prodrugs and solvates of the compound and of its hydroxy acid form and, in particular, said compound, its hydroxy acid form, salts, etc. for use in the prevention of: neurodegenerative diseases, cognitive impairment, diseases associated with undesired oxidation, age-associated pathological processes and progeria, cardiovascular diseases such as atherosclerosis, atrial fibrillation, dyslipidemia, hypercholesterolemia, hyperlipidemia, and hypertriglyceridemia, inflammation or inflammatory processes, or epilepsy, epileptic seizures and convulsions.
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Paragraph 0066-0067
(2013/09/11)
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- Double oxidation of the cyclic nonaketide dihydromonacolin L to monacolin J by a single cytochrome P450 monooxygenase, LovA
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Lovastatin, a cyclic nonaketide from Aspergillus terreus, is a hypercholesterolemic agent and a precursor to simvastatin, a semi-synthetic cholesterol-lowering drug. The biosynthesis of the lovastatin backbone (dihydromonacolin L) and the final 2-methylbutyryl decoration have been fully characterized. However, it remains unclear how two central reactions are catalyzed, namely, introduction of the 4a,5-double bond and hydroxylation at C-8. A cytochrome P450 gene, lovA, clustered with polyketide synthase lovB, has been a prime candidate for these reactions, but inability to obtain LovA recombinant enzyme has impeded detailed biochemical analyses. The synthetic codon optimization and/or N-terminal peptide replacement of lovA allowed the lovA expression in yeast (Saccharomyces cerevisiae). Both in vivo feeding and in vitro enzyme assays showed that LovA catalyzed the conversion of dihydromonacolin L acid to monacolin L acid and monacolin J acid, two proposed pathway intermediates in the biosynthesis of lovastatin. LovA was demonstrated to catalyze the regio- and stereo-specific hydroxylation of monacolin L acid to yield monacolin J acid. These results demonstrate that LovA is the single enzyme that performs both of the two elusive oxidative reactions in the lovastatin biosynthesis.
- Barriuso, Jorge,Nguyen, Don T.,Li, Jesse W.-H,Roberts, Joseph N.,MacNevin, Gillian,Chaytor, Jennifer L.,Marcus, Sandra L.,Vederas, John C.,Ro, Dae-Kyun
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p. 8078 - 8081
(2011/07/08)
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- Synthesis of deuterium-labeled simvastatin
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This study describes the synthesis of deuterium-labeled simvastatin. The stable isotope-labeled compound was prepared starting from lovastatin in nine steps with 9% overall yield.
- Tian, Lei,Tao, Jie,Chen, Liqin
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p. 625 - 628
(2011/12/03)
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- Process for Preparing Substantially Pure Simvastatin
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This invention relates to an improved process for preparing substantially pure simvastatin (I), chemically known as (1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2-H-pyran-2-yl]ethyl]-3 ,7-dimeth-yl-1,2,3,7,8,8a-Hexahydronaphthalen-1-yl2,2-dimethyl butanoate, which comprises of: a) treating lovastatin (II) with an alkali metal hydroxide in a chosen suitable alcoholic solvent followed by relactonization to obtain the diol lactone intermediate (III) in a single vessel. b) selective silylation of 4-hydroxy group of diol lactone intermediate (III) with a chosen suitable silylating reagent to obtain mono silylated intermediate diol lactone (IV). c) acylation of the mono silylated intermediate (IV) to form silylated simvastatin (V) Or optionally, preparing silylated simvastatin (V) starting from Lovastatin (II) without isolating diol lactone (III) and monosilylated diol lactone (IV) and d) finally, removal of the silyl protecting group on silylated simvastatin (V) followed by purification to provide substantially pure simvastatin (I).
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Page/Page column 5
(2011/11/30)
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- Neuroprotective, hypocholesterolemic and antiepileptic compound
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The present invention describes a compound of formula (I) its hydroxy acid form, the pharmaceutically acceptable salts of said hydroxy acid and pharmaceutically acceptable prodrugs and solvates of the compound and of its hydroxy acid form and, in particular, said compound, its hydroxy acid form, salts, etc. for its use in the prevention of: neurodegenerative diseases, cognitive deterioration, diseases associated with undesired oxidation, age-associated pathological processes and progeria, epilepsy, epileptic seizures and convulsions, cardiovascular diseases such as atherosclerosis, atrial fibrillation, dyslipemia, hypercholesterolemia, hyperlipidemia, and hypertriglyceridemia, or fungal or viral infections.
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Page/Page column 12-13
(2010/11/03)
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- Process for Producing Simvastatin
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The present invention discloses a process for producing Simvastatin and intermediate thereof. The present invention uses inexpensive and easily available reagents, its condition is mild, and it leaves out the protective and deprotective steps, which are necessary in prior methods. Compared with prior art, the esterifying condition in 8-position is greatly simplified.
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Page/Page column 6; 9
(2009/03/07)
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- IMPROVED PROCESS FOR PRODUCING SIMVASTATIN
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Disclosed herein is an industrially feasible process for producing HMG-CoA reductase inhibitor, simvastatin, via an improved acylation process using lovastatin ammonium salt as a starting material. The process comprising treating lovastatin ammonium salt with a base to obtain the compound of formula [III], lactonizing the compound of the formula [III] to obtain compound of formula [IV], selectively protecting the hydroxyl group of the compound of formula [IV] to obtain compound of formula [V], acylating the compound of formula [V] with dimethylbutyrylchloride using potassium halide in presence of a solvent to obtain compound of formula [VI], deprotecting compound of formula [VI] followed by hydrolysis to obtain simvastatin ammonium salt of formula [VII] which is lactonized to obtain simvastatin.
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Page/Page column 4; 7
(2008/06/13)
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- METHODS FOR MAKING SIMVASTATIN AND INTERMEDIATES
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The invention provides synthetic chemical and chemoenzymatic methods of producing simvastatin and various intermediates. In one aspect, enzymes such as hydrolases, e.g., esterases, are used in the methods of the invention.
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Page/Page column 64-66
(2008/06/13)
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- PROCESS FOR PREPARING SIMVASTATIN.
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The present invention relates to a process for preparing simvastatin, comprising the steps of reacting a diol lactone of formula 4 with a di-substituted silyl dichloride (dichlorosilane) to produce a diol lactone dimer of formula 5, subsequently acylating the diol lactone dimer with 2,2-dimethylbutyryl chloride to produce a simvastatin dimer of formula 6, and deprotecting the simvastatin dimer to produce simvastatin. The process is simple in overall manufacturing steps, uses cheap protecting agent, and has an excellent productivity and economical effect.
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Page/Page column 9
(2010/02/12)
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- An improved method of symbastatine
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The present invention relates to an improved process for preparing simvastatin and more particularly, the improved process for preparing simvastatin expressed by formula 1 with high yield and high purity by performing the following sequential processes comprising: (i) hydrolysis of lovastatin as starting material with potassium t-butoxide in an organic solvent and small amount of water under a mild reaction condition, followed by lactonization of the obtained solid intermediate with preventing from formation of by-products; (ii) protection of an alcohol group with t-butyldimethylsilyl group which can be easily removed with concentrated hydrochloric acid without the formation of by-products; (iii) acylation of the obtained protected intermediate with acyloxytriphenyl phosphonium salt as an acylating agent under a mild reaction condition; and (iv) removal of the silyl protective group with a concentrated hydrochloric acid. The present invention is to provide the improved process of preparing simvastatin expressed by formula 1 environmentally sound, economically efficient, and industrially useful.
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- METHOD OF PREPARING STATINS INTERMEDIATES
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Provided is a method for preparing a simvastatin intermediate. The method includes hydrolysis of mevinolinic acid as a starting material, lactonization, and protection of a hydroxy group of a lactone ring. Therefore, process steps are reduced and the simvastatin intermediate is produced in high yield.
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- Transformations of cyclic nonaketides by Aspergillus terreus mutants blocked for lovastatin biosynthesis at the lovA and lovC genes
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Two mutants of Aspergillus terreus with either the lovC or lovA genes disrupted were examined for their ability to transform nonaketides into lovastatin 1, a cholesterol-lowering drug. The lovC disruptant was able to efficiently convert dihydromonacolin L 5 or monacolin J 9 into 1, and could also transform desmethylmonacolin J 15 into compactin 3. In contrast, the lovA mutant has an unexpectedly active β-oxidation system and gives only small amounts of 1 upon addition of the immediate precursor 9, with most of the added nonaketide being degraded to heptaketide 22. Similarly, the lovA mutant does not accumulate the polyketide synthase product 5 and rapidly degrades any 5 added as a precursor via two cycles of β-oxidation and hydroxylation at C-6 to give 20. The possible involvement of epoxides 21a and 21b in the biosynthesis of 1 was also examined, but their instability in fermentation media and fungal cells will require purified enzymes to establish their role.
- Sorensen, John L.,Auclair, Karine,Kennedy, Jonathan,Hutchinson, C. Richard,Vederas, John C.
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- Conversion of cyclic nonaketides to lovastatin and compactin by a lovC deficient mutant of Aspergillus terreus
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Investigation of the post-PKS biosynthetic steps to the cholesterol-lowering agent lovastatin (1) using an Aspergillus terreus strain with a disrupted lovC gene, which is essential for formation of 4a,5-dihydromonacolin L (3), shows that 7 and 3 are precursors to 1, and demonstrates that lovastatin diketide synthase (lovF protein) does not require lovC.
- Auclair, Karine,Kennedy, Jonathan,Hutchinson, C. Richard,Vederas, John C.
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p. 1527 - 1531
(2007/10/03)
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- Macrocyclic lactone HMG-CoA reductase inhibitors
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Novel 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors which are useful as antihypercholesterolemic agents and are represented by the following general structural formula (I): STR1 are disclosed. Also disclosed are pharmaceutical compositions and methods of use of the compounds of formula (I).
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- Novel HMG-CoA reductase inhibitors
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Novel 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors which are useful as antihypercholesterolemic agents and are represented by the following general structural formulae (I) or (II): STR1 wherein: n is 1 to 5; R is hydrogen or STR2 R1 is hydrogen or methyl; R2 is hydrogen or methyl; and R3 is hydrogen, C1-5 alkyl or C1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and the dotted lines at a, b and c represent optional double bonds and pharmaceutically acceptable salts of the compounds (II) in which R3 is hydrogen are disclosed.
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