3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.

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Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11β-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.

The first generation peroxisome proliferator-activated receptor (PPAR) ␣ agonist gemfibrozil reduces the risk of major cardiovascular events; therefore, more potent PPAR␣ agonists for the treatment of cardiovascular diseases have been actively sought. We describe two novel, potent oxybenzylglycine PPAR␣-selective agonists, [[5-[[2-(4-, that robustly increase apolipoprotein (Apo) A1 and high-density lipoprotein cholesterol in human ApoA1 transgenic mice and lower low-density lipoprotein-cholesterol and triglycerides in fat-fed hamsters. These compounds have much lower potency against mouse PPAR␣ than human PPAR␣; therefore, they were tested in PPAR␣-humanized mice that do not express murine PPAR␣ but express human PPAR␣ selectively in the liver. We developed hepatic gene induction as a novel biomarker for efficacy and demonstrate hepatic gene induction at very low doses of these compounds. BMS-711939 induces fecal cholesterol excretion, which is further increased upon cotreatment with a liver X receptor (LXR) agonist. It is surprising that this synergistic increase upon coadministration is also observed in mice that express PPAR␣ in the liver only. BMS-711939 also prevented the LXR agonist-induced elevation of serum triglycerides. Such PPAR␣ agonists could be attractive candidates to explore for the treatment of cardiovascular diseases, especially in combination with a suitable LXR agonist.Cardiovascular disease is the leading cause of death for adults in the United States and other developed countries.High low-density lipoprotein-cholesterol (LDLc) and triglycerides and low high-density lipoprotein-cholesterol (HDLc) are prominent risk factors for atherosclerosis. Although considerable progress has been made in lowering LDL-cholesterol by therapeutic means (especially with statins), atherosclerosis still remains a leading cause of mortality. Several clinical studies such as the Scandinavian Simvastatin Survival Study (4S) Group (1994) and Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group (1998) indicate the benefit of lowering LDLc (Linsel-Nitschke and Tall, 2005). Moderate lifelong reduction in LDLc levels in patients with a mutation in the proprotein convertase 1

The enantiospecific and regioselective rhodium-catalyzed allylic alkylation of a series of chiral nonracemic allylic carbonates, followed by ozonolysis and reductive lactonization, provides a convenient route to optically active gamma-lactones. Sequential alkylation and reductive alkylation furnished the alpha-quaternary-beta-ternary substituted gamma-lactone derivative as a >/=10:1 mixture of diastereoisomers.