Modulators of dyslipidaemia

Three-Dimensional Quantitative Structure-Activity Relationship Analysis of Human CYP51 Inhibitors

“…Likewise, if human CYP51 is pursued as a therapeutic target, for example, in cancer (Downie et al, 2005;Kumarakulasingham et al, 2005), this pharmacophore model enables mining of compound data bases for inhibitors and may help in understanding the affinity of inhibitors for the human CYP51 active site. Specific inhibitors of human CYP51 (Harwood et al, 2005) might also be applicable, for example, as agents for lipid lowering, either alone or in combination with other agents (e.g., 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) currently marketed and/or in development (Harwood and Hamanaka, 1998) for use as therapeutic interventions in areas with substantial medical needs such as coronary heart disease, obesity, and diabetes.…”

A Selective Peroxisome Proliferator-Activated Receptor α Agonist, CP-900691, Improves Plasma Lipids, Lipoproteins, and Glycemic Control in Diabetic Monkeys

“…There were no changes in any of the aforementioned parameters in the vehicle group. Because low HDLC and high triglycerides are well established risk factors for cardiovascular disease, the marked improvements in these parameters, and in glycemic control, body weight, and CRP, suggest that CP-900691 may be of benefit in diabetic and obese or hyperlipidemic populations.The peroxisome proliferator-activated receptors (PPAR␣, PPAR␤, and PPAR␥) are a family of distinct nuclear receptors that associate with key naturally occurring lipid molecules and function as transcription factors in the regulation of carbohydrate and lipid metabolism, among other biological processes (Harwood and Hamanaka, 1998;Corton et al, 2000;Willson et al, 2000;Winegar et al, 2001). The PPARs became recognized as important pharmaceutical targets for the treatment of dyslipidemia, diabetes, and the cardiovascular disorders associated with obesity and the metabolic syndrome, when it was discovered that PPAR␥ was the therapeutic target for the marketed glitazone class of antidiabetic agents (Willson et al, , 2001Picard and Auwerx, 2002) and PPAR␣ was the therapeutic target for the marketed fibrate class of antidyslipidemic agents (Harwood and Hamanaka, 1998;Willson et al, 2000;Winegar et al, 2001).…”

Cp-346086

“…The mechanism of lipid-lowering action of CP-346086 in experimental animals and in humans, that of inhibition of VLDL particle secretion from the liver and VLDL and chylomicron secretion from the intestine after a meal, is distinctly different from the primary mechanisms of action of the currently marketed lipid-lowering agents such as the statins, which inhibit cholesterol production in the liver (46), the fibrates, which stimulate both lipoprotein lipase-mediated triglyceride clearance from the plasma and intracellular fatty acid oxidation (46), and the bile acid sequestrants, which interfere with the enterohepatic recirculation of bile acids (46). Thus, CP-346086 and related MTP inhibitors should be effective in combination with these agents.…”

“…Thus, CP-346086 and related MTP inhibitors should be effective in combination with these agents. A combination with fibrates, and indeed with the more potent peroxisome proliferator-activated receptor ␣ (PPAR␣) agonists in development (46), might be especially attractive, as the PPAR agonist-mediated increases in intrahepatocellular fatty acid oxidation could potentially help in the removal of the triglycerides retained in the liver after MTP inhibition. The increased removal of plasma triglycerides by the fibrates, in combination with the reduced secretion of nascent triglyceriderich lipoproteins by an MTP inhibitor, could potentially lead to an even greater magnitude of VLDL-and LDL-lowering efficacy.…”