ABSTRACT
Aim: To evaluate new chemical entities, based on ferulic acid scaffolds, as reversible myeloperoxidase inhibitors (MPOI). Methodology & results:In silico docking studies are performed with MPO protein as a target for several ferulic acid analogs followed by multiple in vitro assays to validate this approach. Two lead compounds 2a and 3 are identified with optimum docking and IC50 values: -7.95 kcal/mol, 0.9 µM and -8.35 kcal/mol, 8.5 µM, respectively. These MPOIs are able to inhibit oxidation of high-density lipoprotein and further promoted functionality of high-density lipoprotein. Conclusion: Lead analogs are potent MPOIs that exert specific effects on MPO-mediated oxidation as well as inflammatory pathways. It also acts as promoters of cholesterol efflux that sheds light on pharmacological approach in atherosclerosis treatment.
Subject(s)
Arteriosclerosis/drug therapy , Coumaric Acids/pharmacology , Enzyme Inhibitors/pharmacology , Peroxidase/antagonists & inhibitors , Phenols/pharmacology , Arteriosclerosis/metabolism , Coumaric Acids/chemical synthesis , Coumaric Acids/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Docking Simulation , Molecular Structure , Oxidation-Reduction , Peroxidase/metabolism , Phenols/chemical synthesis , Phenols/chemistryABSTRACT
BACKGROUND: Dipeptidyl-peptidase 4 (DPP-4) inhibitors are increasingly used to accomplish glycemic targets in patients with type II diabetes mellitus. Because DPP-4 is expressed in inflammatory cells, we hypothesized that its inhibition will exert favorable effects in atherosclerosis. METHODS AND RESULTS: Male LDLR(-/-) mice (6 weeks) were fed a high-fat diet or normal chow diet for 4 weeks and then randomized to vehicle or alogliptin, a high-affinity DPP-4 inhibitor (40 mg · kg(-1) · d(-1)), for 12 weeks. Metabolic parameters, blood pressure, vascular function, atherosclerosis burden, and indexes of inflammation were obtained in target tissues, including the vasculature, adipose, and bone marrow, with assessment of global and cell-specific inflammatory pathways. In vitro and in vivo assays of DPP-4 inhibition (DPP-4i) on monocyte activation/migration were conducted in both human and murine cells and in a short-term ApoE(-/-) mouse model. DPP-4i improved markers of insulin resistance and reduced blood pressure. DPP-4i reduced visceral adipose tissue macrophage content (adipose tissue macrophages; CD11b(+), CD11c(+), Ly6C(hi)) concomitant with upregulation of CD163. DPP-4 was highly expressed in bone marrow-derived CD11b(+) cells, with DPP-4i downregulating proinflammatory genes in these cells. DPP-4i decreased aortic plaque with a striking reduction in plaque macrophages. DPP-4i prevented monocyte migration and actin polymerization in in vitro assays via Rac-dependent mechanisms and prevented in vivo migration of labeled monocytes to the aorta in response to exogenous tumor necrosis factor-α and DPP-4. CONCLUSION: DPP-4i exerts antiatherosclerotic effects and reduces inflammation via inhibition of monocyte activation/chemotaxis. These findings have important implications for the use of this class of drugs in atherosclerosis.
