Synthesis and evaluation of novel alpha-heteroaryl-phenylpropanoic acid derivatives as PPARalpha/gamma 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.

Effects of modifications of the linker in a series of phenylpropanoic acid derivatives: Synthesis, evaluation as PPARalpha/gamma 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.

Arcuate keratotomy for asymmetrical steep islands after laser in situ keratomileusis and automated lamellar keratoplasty.

PURPOSE: To determine the safety and efficacy of arcuate keratotomy (AK) to reduce or eliminate steep asymmetrical islands after laser in situ keratomileusis (LASIK) and automated lamellar keratoplasty (ALK). SETTING: Rancho Bernardo Laser and Vision Center, San Diego, California, USA. METHODS: This retrospective and noncomparative interventional study comprised 8 eyes of 5 patients who received arcuate incisions to reduce topographically defined asymmetrical steep islands after LASIK (n = 7) and ALK for hyperopia (n = 1). The islands occurred unexpectedly after standard excimer laser treatment (VISX Star and S2) for myopic astigmatism that induced irregular astigmatism and unwanted optical effects. Cases occurred consecutively over 16 months, an incidence of less than 1%. Arcuate incisions extended 30 or 45 degrees in LASIK eyes based on the amount of residual refractive astigmatism and were placed at 7.0 mm on the steep axis. Radial incisions were limbal sparing to a 5.0 mm optical zone following the Casebeer nomogram. Outcome measures were uniformity of postenhancement topography, uncorrected visual acuity (UCVA), postenhancement refraction, and reduction in unwanted optical effects. RESULTS: The preenhancement mean spherical equivalent (SE) in the LASIK eyes was -0.99 diopters (D) +/- 0.48 (SD); the astigmatism ranged from 0.50 to 1.75 D. After incisional keratotomy, the mean SE was -0.21 +/- 0.12 D and the net residual astigmatism was reduced to a range of 0 to 0.75 D. All 8 eyes had AK to reduce topographically defined steep islands that were causing visual blurring and unwanted optical effects including ghosting, halos, and polyplopia. After enhancement, there was a marked reduction in the asymmetrical steep islands by topography, fewer unwanted optical effects, less refractive astigmatism, and improved UCVA. Two patients retained small inferior steep areas that may indicate forme fruste keratoconus, although this condition was not detected preoperatively by topographical indices. CONCLUSION: Uncorrected visual acuity improved and unwanted optical effects were reduced after AK on the peripheral axis of asymmetrical steep islands that occurred after uneventful LASIK and hyperopic ALK. This relatively simple incisional approach may be used until more advanced topography-linked ablations with rapid and precise eye tracking are perfected and widely available.