Fluorine-Substitution in Cholesteryl Ester Transfer Protein Inhibitors (CETPInhibitors) – Biology, Chemistry, SAR, and Properties

Abstract

The inhibition of the cholesteryl ester transfer protein (CETP) provides a method for the elevation of the high density lipoprotein cholesterol (HDL-C) level, i.e. the 'good' cholesterol. The expected anti-atherogenic effect of this approach is independent of the proven benefits of lowering the low density lipoprotein cholesterol (LDL-C) level, i.e. the 'bad' cholesterol. A medicinal chemistry project is presented starting from the first screening hit to the second generation development candidate. The structure-activity relationship, the syntheses and the role of fluorine during optimization, as well as the biological activities are discussed.

Oral Cholesteryl Ester Transfer Protein (CETP) Inhibitors: A Potential New Approach for Treating Coronary Artery Disease

“…However, oral administration of 11a in the feed at 0.6 mg/kg for 7 days produced an impressive 57% increase in HDLc and nearly a 20% reduction in LDLc in transgenic mice expressing the human CETP protein. 73 These results compared very favorably with the HDLc elevations of 30-40% reported previously using continuous iv administration of the TP-2 antibody. 55 Pharmacology of Torcetrapib.…”

“…Oral administration of 10a in the feed to New Zealand white rabbits for 3 months at a daily dose of either 50 or 150 mg/kg reduced the atherosclerotic plaque areas in a dosedependent manner by 40% and 70%, respectively, and reduced CE levels in the atherosclerotic fatty streak. 73,113 In this chronic rabbit study, 10a also dose-dependently increased HDLc, which reached a maximal 4-fold increase in the higher dose group, although no changes in LDLc were observed.…”

“…73 Starting from an initial series of highly functionalized 5-hydroxymethylpyridine based 74 and benzyl alcohol based 75 leads, the pentasubstitued pyridine 5a was identified as a lead candidate with nanomolar potency (IC 50 ) 0.013 µM, buffer). In this series, the apical 4-fluorophenyl group at position 4 and the fluorinated 4-trifluoromethylbenzyl moiety at position 3 were retained from earlier series and shown to be important for overall activity.…”

Fluorine in medicinal chemistry: Recent therapeutic applications of fluorinated small molecules

“…Other active compounds recently reported include the disubstituted 3,3,3-trifluoropropan-2-ol amine (37) (Pfizer) having an IC 50 of 0.77 nM in buffer, 59 nM in human serum [61]. Highly fluorinated pyridines 38, 39, and 40 were reported by Bayer A.G. [62]. Potent inhibitors 41 (R = F) and 42 (R = phenoxy) claimed in a recent patent are based on another aminoalcohol scaffold and the tetrazole 43 claimed by Japan Tobacco Inc. has good in vivo activity in hamsters [63] (Fig.…”

“…The Pfizer initiative sought to overcome problems related to rapid metabolism and high lipophilicity associated with the known azole antifungal agents. A series of imidazole derivatives was prepared that were related to ketoconazole (62), an imidazole derivative that was orally active in animal models. In order to bolster resistance to metabolism, the imidazole moiety was replaced with a triazole, and further structural modifications led to UK-47-265 (63), showing outstanding efficacy in model studies.…”