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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Gemfibrozil


Gemfibrozil.svg

Gemfibrozil
CAS: 25812-30-0
 5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic acid
2,2-dimethyl-5-(2,5-xylyloxy)valeric acid
Manufacturers’ Codes: CI-719
Trademarks: Decrelip (Ferrer); Genlip (Teofarma); Gevilon (Pfizer); Lipozid (Pfizer); Lipur (Pfizer); Lopid (Pfizer)
MF: C15H22O3
MW: 250.33
Percent Composition: C 71.97%, H 8.86%, O 19.17%
Properties: Crystals from hexane, mp 61-63°. bp0.02 158-159°. LD50 in mice, rats (mg/kg): 3162, 4786 orally (Kurtz).
Melting point: mp 61-63°
Boiling point: bp0.02 158-159°
Toxicity data: LD50 in mice, rats (mg/kg): 3162, 4786 orally (Kurtz)
Therap-Cat: Antilipemic.
 

Gemfibrozil

5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic Acid

Gemfibrozil is classified as a fibric acid derivative and is used in the treatment of hyperlipidaemias. It has effects on plasma-lipid concentrations similar to those described under bezafibrate. The major effects of gemfibrozil have been a reduction in plasma-triglyceride concentrations and an increase in high-density lipoprotein (HDL) cholesterol concentrations. A reduction in very-low-density lipoprotein (VLDL)-triglyceride appears to be largely responsible for the fall in plasma triglyceride although reductions in HDL and low-density lipoprotein (LDL)-triglycerides have also been reported.
The effects of gemfibrozil on total cholesterol have been more variable: in general, LDL-cholesterol may be decreased in patients with pre-existing high concentrations and raised in those with low concentrations. The increase in HDL-cholesterol concentrations has resulted in complementary changes to the ratios of HDL-cholesterol to LDL-cholesterol and to total cholesterol. Gemfibrozil has successfully raised HDL-cholesterol concentrations in patients with isolated low levels of HDL-cholesterol but otherwise normal cholesterol concentrations.The Helsinki heart study assessed gemfibrozil for the primary prevention of ischaemic heart disease in middle-aged men with hyperlipidaemia. The usual dose, by mouth, is 1.2 g daily in two divided doses given 30 min before the morning and evening meals. Gemfibrozil is available as tablets for oral administration (Lopid: USP).

IR (KBr, cm–1): 2959.03, 2919.78, 2877.65, 1709.42, 1613.44, 1586.60, 1511.07, 1473.81, 1414.01, 1387.89, 1317.61, 1286.34, 1271.91, 1214.39, 1159.26, 1048.83, 996.57, 803.75;

1H NMR (DMSO, 500 MHz, δ ppm): 1.12 (s, 6H), 1.60 and 1.67 (m, 4H), 2.08 (s, 3H), 2.24 (s, 3H), 3.90 (t, 2H), 6.62 (d, 1H), 6.70 (s, 1H), 6.97 (d, 1H);

13C NMR and DEPT (DMSO, 500 MHz, δ ppm): 15.39 (CH3), 20.94 (CH3), 24.67 (CH2), 24.87 (CH3, CH3), 36.43 (CH2), 40.91 (C), 67.57 (CH2), 112.07 (CH), 120.45 (CH), 122.44 (C), 129.96 (CH), 135.93 (C), 156.43 (C), 178.56 (C);

MS M/Z (ESI): 251.16 [(MH)+].

STR1

Solvent:CDCl3Instrument Type:JEOLNucleus:1HFrequency:400 MHzChemical Shift Reference:TMS

 

1H NMR spectrum of C15H22O3 in CDCL3 at 400 MHz

Gemfibrozil is the generic name for an oral drug used to lower lipid levels. It belongs to a group of drugs known as fibrates. It is most commonly sold as the brand name, Lopid. Other brand names include Jezil and Gen-Fibro.

history

Gemfibrozil was selected from a series of related compounds synthesized in the laboratories of the American company Parke Davisin the late 1970s. It came from research for compounds that lower plasma lipid levels in humans and in animals.[1]

Actions

Therapeutic effects

Nontherapeutic effects and toxicities

Indications

Contraindications and precautions

  • Gemfibrozil should not be given to these patients:
    • Hepatic dysfunction
  • Gemfibrozil should be used with caution in these higher risk categories:
    • Biliary tract disease
    • Renal dysfunction
    • Pregnant women
    • Obese patients

Drug interactions

Environmental data

Gemfibrozil has been detected in biosolids (the solids remaining after wastewater treatment) at concentrations up to 2650 ng/g wet weight.[3] This indicates that it survives the wastewater treatment process.

SYNTHESIS

STR1

The sodium isobutyrate (I) is metallated with lithium diisopropylamide, and the resulting compound is alkylated with 3- (2,5-dimethylphenoxy) propyl bromide.

PATENT

Paul, L. C. 2,2-Dimethyl-ω-aryloxy alkanoic acids and salts and ester thereof. U.S. 3,674,836, 1972.

http://www.google.co.in/patents/US3674836

CLIP

Production of Gemfibrozil
(1)2,5-Dimethylphenol and 1-Bromo-3-chloropropane reaction of 1-(2,5-dimethylphenoxy)-3-chloropropane. The reaction is carried out in toluene, adding new clean off reflux 5h. Just as follows:

Production of Gemfibrozil

(2)N/A can be used to manufacture Gemfibrozil.

Production of Gemfibrozil

PAPER

Improved Process for Preparation of Gemfibrozil, an Antihypolipidemic

Chemical Research and Development, Aurobindo Pharma Ltd., Survey No. 71 and 72, Indrakaran (V), Sangareddy (M), Medak District-502329, Andhra Pradesh, India
Engineering Chemistry Department, AU College of Engineering, Andhra University, Visakhapatnam-530003, Andhra Pradesh, India
Org. Process Res. Dev., 2013, 17 (7), pp 963–966

An improved process for the preparation of gemfibrozil, an antihypolipodimic drug substance, with an overall yield of 80% and ∼99.9% purity (including three chemical reactions) is reported. Formation and control of possible impurities are also described. Finally, gemfibrozil is isolated from water without any additional solvent purification.

STR1

Literature References:

Serum lipid regulating agent. Prepn: P. L. Creger, DE 1925423; eidem, US 3674836 (1969, 1972, both to Parke, Davis).

Production: O. P. Goel, US 4126637 (1978 to Warner-Lambert).

Pharmacology: A. H. Kissebach et al.,Atherosclerosis 24, 199 (1976); M. T. Kahonen et al., ibid. 32, 47 (1979).

Series of articles on metabolism, clinical pharmacology, kinetics and toxicology: Proc. R. Soc. Med. 69, Suppl 2, 1-120 (1976).

Toxicity data: S. M. Kurtz et al., ibid. 15.

Clinical trial in hyperlipidemia: J. E. Lewis et al., Pract. Cardiol. 9, 99 (1983).

Clinical reduction of cardiovascular risk in patients with low HDL levels: H. B. Rubins et al., N. Engl. J. Med. 341, 410 (1999).

References

External links

Gemfibrozil
Gemfibrozil.svg
Systematic (IUPAC) name
5-(2,5-dimethylphenoxy)-2,2-dimethyl-pentanoic acid
Clinical data
Trade names Lopid
AHFS/Drugs.com Monograph
MedlinePlus a686002
Pregnancy
category
  • Category C
Routes of
administration
Oral
Legal status
Legal status
  • By Prescription
Pharmacokinetic data
Bioavailability Close to 100%
Protein binding 95%
Metabolism Hepatic (CYP3A4)
Biological half-life 1.5 hours
Excretion Renal 94%
Feces 6%
Identifiers
CAS Number 25812-30-0 Yes
ATC code C10AB04 (WHO)
PubChem CID 3463
IUPHAR/BPS 3439
DrugBank DB01241 Yes
ChemSpider 3345 Yes
UNII Q8X02027X3 Yes
KEGG D00334 Yes
ChEBI CHEBI:5296 Yes
ChEMBL CHEMBL457 Yes
Chemical data
Formula C15H22O3
Molar mass 250.333 g/mol

LOPID® (gemfibrozil tablets, USP) is a lipid regulating agent. It is available as tablets for oral administration. Each tablet contains 600 mg gemfibrozil. Each tablet also contains calcium stearate, NF; candelilla wax, FCC; microcrystalline cellulose, NF; hydroxypropyl cellulose, NF; hypromellose, USP; methylparaben, NF; Opaspray white; polyethylene glycol, NF; polysorbate 80, NF; propylparaben, NF; colloidal silicon dioxide, NF; pregelatinized starch, NF. The chemical name is 5-(2,5-dimethylphenoxy)2,2-dimethylpentanoic acid, with the following structural formula:

 

LOPID® (gemfibrozil) Structural Formula Illustration

The empirical formula is C15H22O3 and the molecular weight is 250.35; the solubility in water and acid is 0.0019% and in dilute base it is greater than 1%. The melting point is 58° –61°C. Gemfibrozil is a white solid which is stable under ordinary conditions.

/////////Gemfibrozil,  Antilipemic,  Fibrates, 25812-30-0,

CC1=CC(OCCCC(C)(C)C(O)=O)=C(C)C=C1

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TORCETRAPIB Revisted


Torcetrapib
Torcetrapib
CAS : 262352-17-0
(2R,4S)-4-[[[3,5-Bis(trifluoromethyl)phenyl]methyl](methoxycarbonyl)amino]-2-ethyl-3,4-dihydro-6-(trifluoromethyl)-1(2H)-quinolinecarboxylic acid ethyl ester
(2R,4S)-4-[(3,5-bis-trifluoromethylbenzyl)methoxycarbonylamino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester
Manufacturers’ Codes: CP-529414
Molecular Formula: C26H25F9N2O4
Molecular Weight: 600.47
Percent Composition: C 52.01%, H 4.20%, F 28.48%, N 4.67%, O 10.66%
Properties: Anhydrous, non-hygroscopic crystals, mp 89-90°. d 1.406.
Melting point: mp 89-90°
Density: d 1.406
 
Derivative Type: Ethanolate
CAS Registry Number: 343798-00-5
Molecular Formula: C26H25F9N2O4.C2H6O
Molecular Weight: 646.54
Percent Composition: C 52.02%, H 4.83%, F 26.45%, N 4.33%, O 12.37%
Properties: White crystalline powder, mp 54-58°. [a]D -93.3° (c = 1.08 in methanol). d 1.402. Non-hygroscopic. Higher aqueous soly than anhydrous form.
Melting point: mp 54-58°
Optical Rotation: [a]D -93.3° (c = 1.08 in methanol)
Density: d 1.402
Therap-Cat: Antilipemic; antiatherosclerotic.
 Torcetrapib.png

Torcetrapib (CP-529,414, Pfizer) was a drug being developed to treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular disease. Its development was halted in 2006 when phase III studies showed excessive all-cause mortality in the treatment group receiving a combination of atorvastatin (Lipitor) and torcetrapib.

 

Medical uses

Torcetrapib has not been found to affect either cardiovascular disease or risk of death in those already taking a statin.[1]

Mechanism

Torcetrapib acts (as a CETP inhibitor) by inhibiting cholesterylester transfer protein (CETP), which normally transfers cholesterol from HDL cholesterol to very low density or low density lipoproteins (VLDL or LDL). Inhibition of this process results in higher HDL levels (the “good” cholesterol-containing particle) and reduces LDL levels (the “bad” cholesterol).[vague][citation needed]

Development

The first step in the synthesis was a recently created reaction of amination to p-chlorotrifluoryltoluene, a reaction that was created by Dr. Stephen Buchwald at MIT.[2]

Development of the drug began around 1990; it was first administered in humans in 1999, and manufacturing at production scale began in Ireland in 2005.[3]

Pfizer had previously announced that torcetrapib would be sold in combination with Pfizer’s statin, atorvastatin (Lipitor); however, following media and physician criticism, Pfizer had subsequently planned for torcetrapib to be sold independently of Lipitor.[4]

Clinical trials

A 2004 trial (19 subjects, non-randomised) showed that torcetrapib could increase HDL and lower LDL with and without an added statin.[5]

Nine phase III studies were completed.[6][7][8][9][10][11][12][13][14][15]

Early termination of study

On December 2, 2006 Pfizer cut off torcetrapib’s phase III trial because of “an imbalance of mortality and cardiovascular events” associated with its use.[16] This was a sudden and unexpected event and as late as November 30, 2006 Jeff Kindler, Pfizer’s chief executive, was quoted, “This will be one of the most important compounds of our generation.”[16] In the terminated trial, a 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin versus taking atorvastatin alone.[17] Pfizer recommended that all patients stop taking the drug immediately.[18]

Six studies were terminated early.[6] One of the completed studies found it raised systolic blood pressure and concluded “Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further.”[19]

The drug cost $800m+ to bring into Phase III development.[20]

 09008-cover-cetrapib
 Dec. 2, 2006, was a day drugmakers won’t soon forget. On that day, Pfizer, the world’s biggest drug company, faced devastating news: Its highest profile drug candidate, the cholesterol-targeted molecule torcetrapib, had increased the risk of death in a 15,000-patient clinical trial. In light of the data, Pfizer promptly pulled the plug on the cholesteryl ester transfer protein (CETP) inhibitor that already had cost more than $800 million to develop. The torcetrapib news rocked the cardiovascular research field and left Pfizer without a potential new medication to supplement the blockbuster cholesterol drug Lipitor (atorvastatin), which was careening toward the patent cliff.
 
 
……………………
A Concise Asymmetric Synthesis of Torcetrapib�, M. Guino, P. H. Phua, J-C. Caille and K. K. Hii, J. Org. Chem., 2007, 72, 6290-6293.doi:10.1021/jo071031gAbstract: Optically active torcetrapib was synthesized in seven steps from achiral precursors without the need for protecting groups, utilizing an enantioselective aza-Michael reaction to achieve asymmetry.

 ………………………..
PATENT

Example 9 Anhydrous, (-)-(2R,4S)-4-[(3,5-Bιs-trιfluoromethyl-benzyl)-methoxycarbonyl-amιnol-2- ethyl-6-trιfluoromethyl-3,4-dιhydro-2H-quιnolιne-1 -carboxylic acid ethyl ester.

A 2.6g portion of 4(S)-[(3,5-bιs-tπfluoromethyl-benzyl)-methoxycarbonyl-amιno]-2(R)- ethyl-6-tπfluoromethyl-3,4-dιhydro-2H-quιnolιne-1 -carboxylic acid ethyl ester (a mixture of predominantly amorphous material with traces of ethanolate crystalline form; the title compound was also prepared in an analogous manner starting from pure amorphous or pure ethanolate material) was charged to 13 milliliters of hexanes and heated to effect a solution at about 60°C The heat was removed and the reaction was allowed to cool to ambient over a one hour period The reaction was seeded with anhydrous (-)-(2R,4S)-4-[(3,5-bιs-tπfluoromethyl-benzyl)- methoxycarbonyl-amιno]-2-ethyl-6-trιfluoromethyl-3,4-dιhydro-2H-quιnolιne-1 – carboxylic acid ethyl ester and granulated for eighteen hours under ambient conditions. Alternately, the anhydrous crystals may be prepared from hexanes without seeding. The product was collected by filtration and air dried. The isolated product X-ray pattern matched the calculated powder pattern. Density: 1.406 Crystal System: Trigonal

Microscopy: Well formed rods and equant (fractured rods) crystals demonstrating high birefringence when viewed across the C axis. Being in the Trigonal crystal system the crystals do not demonstrate birefringence when viewed down the C axis. The crystals demonstrate a cleavage plane perpendicular to the C axis Fusion Microsocopy In Type A oil dissolution at 50°C.

Dry — clear melt at 86°C.

NMR: No trace of ethanolate

Degree of crystallmity: Highly crystalline Hygroscopicity. Non-hygroscopic at 100% relative humidity over 48 hours.

Appearance: Free flowing white powder

 
Lit References:
Cholesteryl ester transfer protein (CETP) inhibitor. Prepn: M. P. DeNinno et al., WO 0017164; eidem, US6197786 (2000, 2001 both to Pfizer); of crystalline forms: D. J. M. Allen et al., WO 0140190 (2001 to Pfizer).
Mechanism of action study: R. W. Clark et al., J. Lipid Res. 47, 537 (2006).
Clinical evaluation of effects on HDL cholesterol levels: R. W. Clark et al.,Arterioscler. Thromb. Vasc. Biol. 24, 490 (2004); M. E. Brousseau et al., N. Engl. J. Med. 350, 1505 (2004).
Review of clinical development in combination with atorvastatin: J. R. Burnett, Curr. Opin. Invest. Drugs 6, 944-950 (2005).

References

Notes

  1.  Keene, D; Price, C; Shun-Shin, MJ; Francis, DP (Jul 18, 2014). “Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients.”. BMJ (Clinical research ed.) 349: g4379. PMID 25038074.
  2.  Buchwald, Stephen (July 23, 2004). “Research Projects”. Retrieved 2007-10-04.
  3. “Pfizer Begins Production at Torcetrapib/Atorvastatin Manufacturing Facility” (Press release). Pfizer. June 22, 2005. Retrieved 2006-12-03.
  4.  Berenson, Alex (July 26, 2006). “Heart Pill to Be Sold by Itself”. Business (The New York Times). Retrieved 2006-12-03.
  5. Brousseau, ME; Schaefer EJ; Wolfe ML; Bloedon LT; Digenio AG; Clark RW; Mancuso JP; Rader DJ (April 8, 2004). “Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol” (abstract). New England Journal of Medicine 350 (15): 1505–1515. doi:10.1056/NEJMoa031766. PMID 15071125. Retrieved 2006-12-03.
  6.  http://clinicaltrials.gov/ct2/results?term=torcetrapib
  7.  http://clinicaltrials.gov/ct2/show/NCT00139061 Phase III Assess HDL-C Increase And Non-HDL Lowering Effect Of Torcetrapib/Atorvastatin Vs. Fenofibrate
  8.  http://clinicaltrials.gov/ct2/show/NCT00134511 Phase III Study To Evaluate The Effect Of Torcetrapib/Atorvastatin In Patients With Genetic High Cholesterol Disorder
  9.  http://clinicaltrials.gov/ct2/show/NCT00134485 Phase III Study To Evaluate The Safety And Efficacy Of Torcetrapib/Atorvastatin In Subjects With Familial Hypercholerolemia
  10.  http://clinicaltrials.gov/ct2/show/NCT00134498 Phase III Study Comparing The Efficacy & Safety Of Torcetrapib/Atorvastatin And Atorvastatin In Subjects With High Triglycerides
  11.  http://clinicaltrials.gov/ct2/show/NCT00267254 Phase III Clinical Trial Comparing Torcetrapib/Atorvastatin To Simvastatin In Subjects With High Cholesterol
  12.  http://clinicaltrials.gov/ct2/show/NCT00138762 Phase III Study of Torcetrapib/Atorvastatin vs Atorvastatin Alone or Placebo in Patients With High Cholesterol
  13. http://clinicaltrials.gov/ct2/show/NCT00134173 Phase III Coronary IVUS Study to Compare Torcetrapib/Atorvastatin to Atorvastatin Alone in Subjects With Coronary Heart Disease (ILLUSTRATE)
  14.  http://clinicaltrials.gov/ct2/show/NCT00137462 Phase III Lipitor Trial To Study The Effect Of Torcetrpib/Atorvastatin To Atorvastatin Alone.
  15.  http://clinicaltrials.gov/ct2/show/NCT00136981 Phase III Carotid B-Mode Ultrasound Study to Compare Anti-Atherosclerotic Effect of Torcetrpib/Atorvastatin to Atorvastatin Alone. (RADIANCE 1)
  16.  Berenson, Alex (December 3, 2006). “Pfizer Ends Studies on Drug for Heart Disease”. The New York Times. Retrieved 2006-12-03. (registration required)
  17.  Theresa Agovino (Associated Press) (December 3, 2006). “Pfizer ends cholesterol drug development”. Yahoo! News. Retrieved 2006-12-03.[dead link] Each study arm (torcetrapib + atorvastatin vs. atorvastatin alone) had 7500 patients enrolled; 51 deaths were observed in the atorvastatin alone arm, while 82 deaths occurred in the torcetrapib + atorvastatin arm. (Link dead as of 15 January 2007)
  18. Associated Press (December 2, 2006). “Pfizer cuts off cholesterol drug trials”. Yahoo! News (Yahoo.com). Retrieved 2006-12-03.[dead link] (Link dead as of 15 January 2007)
  19.  Bots et al.; Visseren, Frank L; Evans, Gregory W; Riley, Ward A; Revkin, James H; Tegeler, Charles H; Shear, Charles L; Duggan, William T et al. (July 2007). “Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial”. The Lancet 370 (9582): 153–160. doi:10.1016/S0140-6736(07)61088-5.
  20. Cutler, D. M. (2007-03-29). “The Demise of the Blockbuster?”. The New England Journal of Medicine (Massachusetts Medical Society) 356 (13): 1292–1293. doi:10.1056/NEJMp078020.ISSN 1533-4406. PMID 17392299. Retrieved 2007-04-23.

External links

Keywords: Antilipemic; CETP Inhibitor; Antiatherosclerotic.
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