Hypolipidemic agents

Saponins. Although the hypocholesterolemic activity of saponins has been known since the 1950s, thek low potency and difficult purification sparked Htde interest in natural saponins as hypolipidemic agents. Synthetic steroids (292, 293) that are structurally related to saponins have been shown to lower plasma cholesterol in a variety of different species (252). Steroid (292) is designated CP-88,818 [99759-19-0]. The hypocholesterolemic agent CP-148,623 [150332-35-7] (293) is not absorbed into the systemic ckculation and does not inhibit enzymes involved in cholesterol synthesis, release, or uptake. Rather, (293) specifically inhibits cholesterol absorption into the intestinal mucosa (253). As of late 1996, CP-148,623 is in clinical trials as an agent that lowers blood concentrations of cholesterol (254). 

Tibric acid (10), interestingly, has the m-carboxysulfonamido functionality but its activity is expressed, instead, as suppression of serum triglyceride levels. In its reported preparation, chloro-sulfonic acid treatment converts 2-chlorobenzoic acid to chlorosulfonate 9, which readily forms the hypolipidemic agent tibric acid (10) on reaction with... 

The recent years have seen the success of statins like Lipitor (atorvastatin) as hypolipidemic agents that help treating cardiovascular disease primarily by lowering low-density lipoproteins ( bad cholesterol ) levels. Another novel strategy is to tackle the same problem by elevating high-density lipoproteins (H D L or good cholesterol ) levels via inhibition of cholesteryl ester transfer protein (CETP). 

H. Hall, D. J. Reynolds, S. D. Wyrick, J. H. Maguire, R. P. Shrewsbury, The Disposion of the Hypolipidemic Agent o-lA-Phthahmido (acetophenone, in Sprague-Dawley Rats , Drug Metab. Dispos. 1988, 16, 196-200. 

Roth, B. D., The discovery and development of atorvastatin, a potent novel hypolipidemic agent. Prog. Med. Chem., 2002, 40, 1-22 and references cited therein. 

Ciprofibrate 131 is a potent, long-acting hypolipidemic agent. It is effective in type Ila, Ilb, III and IV hyperlipoproteinemias and produces a beneficial elevation of the anti-atherogenic high density lipoprotein, Eq. (52) [182]. 

These hypolipidemic agents are noncompetitive inhibitors of the enzyme that limit the rate of cholesterol synthesis in the liver at the levalonic acid stage. 

Cholesterol Transport Protein Inhibitor Ezetimibe is the first hypolipidemic agent to act by blocking the absorption of dietary cholesterol at the intestinal level. It represents a novel treatment option for patients with hypercholesterolemia, alone or in combination with statins (Figure 8.60). 

Fisher DA, Elias PM, LeBoit PL. Exacerbation of psoriasis by the hypolipidemic agent, gemfibrozil. Arch Dermatol 1988 124(6) 854-5. 

Horn M. Coadministration of itraconazole with hypolipidemic agents may induce rhabdomyolysis in healthy individuals. Arch Dermatol 1996 132(10) 1254. 

A PK/PD relationship in humans has recently been reported for a novel hypolipidemic agent, ISIS 301012, a 2 -MOE partially modified antisense inhibitor of human apoB-100 [59, 64]. ApoB-100 is a structural component of LDL-cholesterol, and plays a key role in its metabolism and transport Prefiminary data from this study indicate that antisense inhibition of apoB-100 results in both dose- and concentration-dependent sustained reductions in serum levels of apoB-100, LDL-cho-lesterol and total cholesterol, but does not affect levels of HDL-cholesterol. 

Staubli W, Hess R. 1975. Lipoprotein formation mthe liver cell. Ultrastructural and functional aspects relevant to hypolipidemic action. In Kritchersky D, ed. Handbook of experimental pathology, VoL 41. Hypolipidemic/agents. Berlin Springer-Verlag, 229-289. 

I. In Vivo Assay of Hypolipidemic Agents Using Hyperlipidemic Hamsters... 

In conjunction with a statin such as simvastatin, l,3-diaryl-2-pyridin-2-yl-3-(pyridin-2-ylamino)propanol derivatives, (IV), prepared by Kirsch (5) were effective as hypolipidemic agents in the treatment of arteriosclerosis. 

The discovery of the statin mevalonic acid synthesis inhibitors focused new attention on control of blood lipid levels as a measure to stave off heart disease. A number of compounds have been found that treat elevated lipid levels by other diverse mechanisms. The phosphonic acid derivative ibrolipim (9) is believed to lower those levels by accelerating fatty acid oxidation. The phosphoms-containing starting material 7 can in principle be obtained by the Arbuzov reaction of a protected from of p-bromomethylbenzoic acid (6) with triethyl phosphate. Removal of the protecting group and conversion of the acid to an acyl chloride then affords 7. Condensation of this intermediate with substituted aniline 8 leads to the hypolipidemic agent (9). ... 

M.R. Munday and C.J. Hemingway. 1999. The regulation of acetyl-CoA carboxylase A potential target for the action of hypolipidemic agents Hc/v. Enzyme Regul. 39 205-234. (PubMed)... 

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