ABSTRACT
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a potential novel strategy for treatment of CVD. Alirocumab is a fully human PCSK9 monoclonal antibody in phase 3 clinical development. We evaluated the antiatherogenic potential of alirocumab in APOE*3Leiden.CETP mice. Mice received a Western-type diet and were treated with alirocumab (3 or 10 mg/kg, weekly subcutaneous dosing) alone and in combination with atorvastatin (3.6 mg/kg/d) for 18 weeks. Alirocumab alone dose-dependently decreased total cholesterol (-37%; -46%, P < 0.001) and TGs (-36%; -39%, P < 0.001) and further decreased cholesterol in combination with atorvastatin (-48%; -58%, P < 0.001). Alirocumab increased hepatic LDL receptor protein levels but did not affect hepatic cholesterol and TG content. Fecal output of bile acids and neutral sterols was not changed. Alirocumab dose-dependently decreased atherosclerotic lesion size (-71%; -88%, P < 0.001) and severity and enhanced these effects when added to atorvastatin (-89%; -98%, P < 0.001). Alirocumab reduced monocyte recruitment and improved the lesion composition by increasing the smooth muscle cell and collagen content and decreasing the macrophage and necrotic core content. Alirocumab dose-dependently decreases plasma lipids and, as a result, atherosclerosis development, and it enhances the beneficial effects of atorvastatin in APOE*3Leiden.CETP mice. In addition, alirocumab improves plaque morphology.
Subject(s)
Antibodies, Monoclonal/pharmacology , Atherosclerosis/drug therapy , Cholesterol/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Macrophages/metabolism , Monocytes/metabolism , Animals , Antibodies, Monoclonal, Humanized , Atherosclerosis/genetics , Atherosclerosis/metabolism , Atherosclerosis/pathology , Cholesterol/genetics , Dose-Response Relationship, Drug , Drug Synergism , Female , Humans , Macrophages/pathology , Mice , Mice, Transgenic , Monocytes/pathologyABSTRACT
A series of novel, highly potent, achiral factor Xa inhibitors based on a benzoic acid scaffold and containing a chlorophenethyl moiety directed towards the protease S1 pocket is described. A number of structural features, such as the requirements of the P1, P4 and ester-binding pocket ligands were explored with respect to inhibition of factor Xa. Compound 46 was found to be the most potent compound in a series of antithrombotic secondary assays.
Subject(s)
Benzoates/pharmacology , Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Benzoates/chemical synthesis , Blood Coagulation Tests , Drug Stability , Fibrinolytic Agents/pharmacology , Humans , Ligands , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Protein Binding , Structure-Activity RelationshipABSTRACT
The astonishing discovery that peptide nucleic acids (PNAs, B=nucleobase), in spite of their drastic structural difference to natural DNA, are better nucleic acid mimetics than many other oligonucleotides has resulted in an explosion of research into this class of compounds. The synthesis, physical properties, and biological interactions of PNAs as well as their chimeras with DNA and RNA are summarized here.
