Abstract 14992: Identification and Characterization of Orally Bio-Available Anti-Atherosclerosis Agents
Our goal is to develop a new drug to lower the risk of coronary heart disease (CHD) by focusing on the regression and prevention of atherosclerosis. Although much progress has been made in the control of progression of the disease, nonetheless the incidence of atherosclerosis remains high. To address this concern, new strategies were developed for targeting vascular inflammation/atherosclerosis by inhibiting the process that is mediated by endothelial lipase (EL). EL is a member of the triglyceride lipase family that includes lipoprotein lipase (LPL), pancreatic lipase (PL), and hepatic lipase (HL), but unlike LPL and HL, it is synthesized by endothelial cells and functions at the site where it is synthesized. Several reports have shown that the inflammatory cytokines, tumor necrosis factor-alpha (“TNF-α”) and interleukin-1 beta (“IL-1β”) upregulate EL expression, and EL also affects the expression of cytokines, which in turn play an important role in atherogenesis. We have identified several low nM EL inhibitors that possess high selectivity against other lipases. Our novel lead molecule has IC50’s of 14, 12,000, 39,000 and 5,000 nM against EL, PL, LPL and HL, respectively. The Ki of our lead molecule against EL was 3 nM which is in agreement with the above IC50 value. In mice treated with LPS, our lead molecule exhibits good anti-inflammatory effects in that it causes the reduction of the pro-inflammatory stimuli, IL-1β (>3 fold) and eotaxin (>4 fold), and the rise of the natural anti-inflammatory mediator, IL-10 (>2 fold). In addition, administration of our lead molecule to mice fed a high-fat diet, either treated or untreated with LPS, resulted in a 50-80% increase in the level of HDL. The effect of our lead molecule was evaluated further for the progression of atherosclerotic lesions in ApoE-KO male mice. Interestingly, the effect was quite significant in that it decreased atherosclerotic plaque lesions more than 80%. In vivo pharmacokinetic (PK) and pharmacodynamics (PD) evaluation of this compound in mice demonstrated that it is orally efficacious, exhibiting 49% oral bioavailability. Thus, identification of a potent and highly selective small molecule, orally active EL modulator represents a significant advance and opportunity for drug development.
Author Disclosures: N.A. Elshourbagy: Employment; Significant; Shifa Biomedical Corporation. Research Grant; Significant; HL097438. H.V. Meyers: Employment; Significant; Shifa Biomedical Corporation. Research Grant; Significant; HL097438. S.A. Mousa: Research Grant; Significant; HL097438. Consultant/Advisory Board; Significant; Shifa Biomedical Corporation.
- © 2016 by American Heart Association, Inc.