Hilmar Bischoff

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.

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.

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.

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 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.

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.

Glycine amides as PPARα 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.