Prediction of a potentially effective dose in humans for BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP) by allometric species scaling and combined pharmacodynamic and physiologically-based pharmacokinetic modelling.

AIMS: The purpose of this work was to support the prediction of a potentially effective dose for the CETP-inhibitor, BAY 60-5521, in humans. METHODS: A combination of allometric scaling of the pharmacokinetics of the CETP-inhibitor BAY 60-5521 with pharmacodynamic studies in CETP-transgenic mice and in human plasma with physiologically-based pharmacokinetic (PBPK) modelling was used to support the selection of the first-in-man dose. RESULTS: The PBPK approach predicts a greater extent of distribution for BAY 60-5521 in humans compared with the allometric scaling method as reflected by a larger predicted volume of distribution and longer elimination half-life. The combined approach led to an estimate of a potentially effective dose for BAY 60-5521 of 51 mg in humans. CONCLUSION: The approach described in this paper supported the prediction of a potentially effective dose for the CETP-inhibitor BAY 60-5521 in humans. Confirmation of the dose estimate was obtained in a first-in-man study.

Identification of 4H,6H-[2]benzoxepino[4,5-c][1,2]oxazoles as novel squalene synthase inhibitors.

Novel squalene synthase inhibitors are disclosed. The design, synthesis, SAR and pharmacological profile of the compounds are discussed.

Identification and optimization of tetrahydro-2H-3-benzazepin-2-ones as squalene synthase inhibitors.

Novel squalene synthase inhibitors are disclosed. SAR and pharmacological profile of selected compounds are discussed.

Chromanol derivatives--a novel class of CETP inhibitors.

Based on our former development candidate BAY 38-1315, optimization efforts led to the discovery of a novel chemical class of orally active cholesteryl ester transfer protein (CETP) inhibitors. The chromanol derivative 19b is a highly potent CETP inhibitor with favorable pharmacokinetic properties suitable for clinical studies. Chemical process optimization furnished a robust synthesis for a kilogram-scale process.

Cholesteryl ester transfer protein and its inhibition.

Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of cholesteryl esters from the atheroprotective high density lipoprotein (HDL) to the proatherogenic low density lipoprotein cholesterol (LDL) and very low density lipoprotein cholesterol (VLDL) leading to lower levels of HDL but raising the levels of proatherogenic LDL and VLDL. Inhibition of CETP is considered a potential approach to treat dyslipidemia. However, discussions regarding the role of CETP-mediated lipid transfer in the development of atherosclerosis and CETP inhibition as a potential strategy for prevention of atherosclerosis have been controversial. Although many animal studies support the hypothesis that inhibition of CETP activity may be beneficial, negative phase III studies on clinical endpoints with the CETP inhibitor torcetrapib challenged the future perspectives of CETP inhibitors as potential therapeutic agents. The review provides an update on current understanding of the molecular mechanisms involved in CETP activity and its inhibition.

Glycine amides as PPARalpha agonists.

The design, synthesis and pharmacological properties of a novel class of PPARalpha agonists is described. Compound 2 is a novel, potent and specific glycine amide with oral bioavailability in rodents. The compound is active in vivo and alters plasma lipids in hAPO-A1 transgenic mice after oral administration.

Novel tetrahydrochinoline derived CETP inhibitors.

In the course of our efforts to identify orally active cholesteryl ester transfer protein (CETP) inhibitors, we have continued to explore tetrahydrochinoline derivatives. Based on BAY 19-4789 structural modifications led to the discovery of novel cycloalkyl substituted compounds. Thus, example 11b is a highly potent CETP inhibitor both in vitro and in vivo in transgenic mice with favourable pharmacokinetic properties for clinical development.

Novel heterocyclic thyromimetics. Part 2.

Novel heterocyclic thyromimetics are presented carrying carboxy-substituted benzofurans or sulfur containing heterocycles, as replacements for the amino acid side chain of T3. Potent agonists were identified in both series. SAR trends are examined and found to be mostly consistent with previously published thyromimetics. The lack of isoform selectivity demonstrated with isoform-selective transient THR transfection assays has been confirmed by corresponding in vivo studies.

Minor structural modifications convert a selective PPARalpha agonist into a potent, highly selective PPARdelta agonist.

We report the solid-phase synthesis and pharmacological evaluation of a new series of small-molecule agonists of the human peroxisome proliferator-activated receptor delta (PPARdelta) based on a lead structure from our PPARalpha program. Compound 33 showed good pharmacokinetics.

Repetitive postprandial hyperglycemia increases cardiac ischemia/reperfusion injury: prevention by the alpha-glucosidase inhibitor acarbose.

Protective effects of the alpha-glucosidase inhibitor acarbose have been reported for various diabetic complications. In the STOP-NIDDM study, even patients without overt diabetes, but with impaired glucose tolerance, had a reduction in cardiovascular events when treated with acarbose. Therefore, we investigated the effect of repetitive postprandial hyperglycemia on the cardiac ischemia/reperfusion injury in vivo. Mice were treated daily by single applications of placebo, sucrose (4 g/kg body weight), or sucrose + acarbose (10 mg/kg body weight) by gavage for 7 days. Acarbose treatment significantly reduced the sucrose-induced increase in plasma glucose concentration. Subsequently, animals underwent 30 min of ischemia by coronary artery ligation and 24 h of reperfusion in vivo. In the sucrose group, ischemia/reperfusion damage was significantly increased (infarct/area at risk, placebo vs. sucrose, 38.8+/-7.5% vs. 62.2+/-4.8%, P<0.05). This was prevented by acarbose treatment (infarct/area at risk 30.7+/-7.2%). While myocardial inflammation was similar in all groups, oxidative stress as indicated by a significant increase in lipid peroxides was enhanced in the sucrose, but not in the sucrose + acarbose group. In summary, repetitive postprandial hyperglycemia increases ischemia/reperfusion damage. This effect can be prevented by treatment with the alpha-glucosidase inhibitor acarbose.

Increased platelet activation in young Zucker rats with impaired glucose tolerance is improved by acarbose.

Patients with diabetes display increased platelet activation. Recent data show a markedly increased risk for cardiovascular events already in pre-diabetic individuals with impaired glucose tolerance (IGT). We investigated whether IGT is associated with platelet activation. Blood samples were collected from young lean (control) and obese Zucker rats, an established model of IGT, after single oral application of sucrose (4 g.kg-1). Platelet-bound fibrinogen and platelet surface-expression of P-selectin were assessed as indices of platelet activation using flow cytometry. In lean Zucker rats, acute sucrose application induced fibrinogen-binding and P-selectin surface-expression, which was prevented by co-administration of acarbose (10 mg.kg-1). In obese Zucker rats, platelet activation was already maximally increased under baseline conditions with no significant increase after sucrose application. Chronic treatment with acarbose (15 mg.kg-1.day-1) significantly reduced platelet activation in these animals. Acute ingestion of sucrose induces platelet activation which is prevented by acarbose. IGT is associated with marked platelet activation that can be reduced by chronic administration of acarbose. The positive modulation of platelet activation by acarbose may contribute to the reduction of cardiovascular events in patients with IGT.

Early acarbose treatment ameliorates resistance of insulin-regulated GLUT4 trafficking in obese Zucker rats.

Genetically (fa/fa) obese Zucker rats represent an established model of impaired glucose tolerance, with profound insulin resistance. Acarbose, an inhibitor of alpha-glucosidases, attenuates postprandial blood glucose peaks, and improves glucose tolerance in these animals. In the present study, we have tested the hypothesis that the effect of acarbose is associated with improved glucose transporter isoform 4 (GLUT4) trafficking in muscle tissue. Acarbose was administered to Zucker rats as a dietary admix (40 mg/100 g diet) for 12 weeks starting at the age of 6 weeks. Serum insulin and leptin were reduced by acarbose from 44 to 19 and 144 to 62 ng/ml, respectively. Glucose tolerance test was performed by i.v. injection of glucose (1 g/kg) and determination of serum glucose up to 60 min. Marked impaired glucose tolerance was observed in obese animals with a profound correction of this defect in acarbose-treated rats. Insulin-regulated translocation of GLUT4 to the plasma membrane in soleus muscle was increased twofold in lean animals, with a totally blunted response in obese rats. Acarbose feeding restored a 1.6-fold effect of insulin on GLUT4 translocation. The exocytotic GLUT4 storage pool in cardiac muscle was completely insulin-insensitive in obese animals, with a largely improved response after acarbose feeding. Activation of Akt, an insulin signaling event upstream of GLUT4, was completely normalized in acarbose-treated rats. In conclusion, we show here that early application of acarbose to obese Zucker rats can prevent the development of impaired glucose tolerance and obesity-associated insulin resistance at the level of the muscle cell, as reflected by an amelioration of defective GLUT4 trafficking in both cardiac and skeletal muscles.