Bruce Auerbach

The combined effect of inhibiting both ACAT and HMG-CoA reductase may directly induce atherosclerotic lesion regression

We hypothesized that coadministration of avasimibe and simvastatin would limit size, composition and extent of atherosclerotic lesions and potentially promote lesion regression, since bioavailable ACAT inhibitors decrease monocyte-macrophage enrichment and HMG-CoA reductase inhibitors limit smooth muscle cell migration and proliferation. Male New Zealand white rabbits were sequentially fed a 0.5% cholesterol, 3% peanut oil, 3% coconut oil diet for 9 weeks and a chow-fat diet for 6 weeks prior to drug administration. A time zero control group was necropsied prior to drug administration and the progression control was fed various diets but untreated. Avasimibe (10 mg/kg), simvastatin (2.5 mg/kg) or combination of avasimibe (10 mg/kg) with simvastatin (2.5 mg/kg) were administered in the chow-fat diet for 8 weeks. Plasma total cholesterol exposure was unchanged by avasimibe but was reduced 21% by both simvastatin alone and in combination with avasimibe. Combination of avasimibe and simvastatin decreased VLDL-cholesterol exposure by 56%. VLDL+IDL lipid composition was similar in the progression control and simvastatin-treated animals. Administration of avasimibe alone or in combination with simvastatin reduced the cholesteryl ester fraction and increased the triglyceride fraction to comparable extents. Relative to the progression control, avasimibe plus simvastatin markedly decreased thoracic aortic cholesteryl ester content and lesion coverage by 50% and aortic arch lesion size and macrophage area by 75 and 73%, respectively. With respect to lesion regression, avasimibe+simvastatin decreased aortic arch lesion size by 64% and monocyte-macrophage area by 73% when compared to time zero. Based on these data, we conclude that despite changes in plasma total and lipoprotein cholesterol exposure and lipoprotein composition comparable to monotherapy, inhibition of both ACAT and HMG-CoA reductase may not only directly blunt lesion progression but also promote regression of pre-established atherosclerotic lesions.

Effects of modifications of the linker in a series of phenylpropanoic acid derivatives : Synthesis, evaluation as PPARα/γ dual agonists, and X-ray crystallographic studies

A new series of alpha-aryl or alpha-heteroarylphenyl propanoic acid derivatives was synthesized that incorporate acetylene-, ethylene-, propyl-, or nitrogen-derived linkers as a replacement of the commonly used ether moiety that joins the central phenyl ring with the lipophilic tail. The effect of these modifications in the binding and activation of PPARalpha and PPARgamma was first evaluated in vitro. Compounds possessing suitable profiles were then evaluated in the ob/ob mouse model of type 2 diabetes. The propylene derivative 40 and the propyl derivative 53 demonstrated robust plasma glucose lowering activity in this model. Compound 53 was also evaluated in male Zucker diabetic fatty rats and was found to achieve normalization of glucose, triglycerides, and insulin levels. An X-ray crystal structure of the complex of 53 with the PPARgamma-ligand-binding domain was obtained and discussed in this report.

Discovery of novel hepatoselective HMG-CoA reductase inhibitors for treating hypercholesterolemia: a bench-to-bedside case study on tissue selective drug distribution.

The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.

Synthesis and evaluation of novel α-heteroaryl-phenylpropanoic acid derivatives as PPARα/γ dual agonists

The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the alpha-position and their evaluation for binding and activation of PPARalpha and PPARgamma are presented in this report. Among the new compounds, (S)-3-{4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl}-2-1,2,3-triazol-2-yl-propionic acid (17j), was identified as a potent human PPARalpha/gamma dual agonist (EC(50)=0.013 and 0.061 microM, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies.