Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis.

A novel, selective, and efficacious GPR4 antagonist 13 was developed starting from lead compound 1a. While compound 1a showed promising efficacy in several disease models, its binding to a H3 receptor as well as a hERG channel prevented it from further development. Therefore, a new round of optimization addressing the key liabilities was performed and led to discovery of compound 13 with an improved profile. Compound 13 showed significant efficacy in the rat antigen induced arthritis as well as in the hyperalgesia and angiogenesis model at a well-tolerated dose of 30 mg/kg.

Changes in carotid artery flow velocities after stent implantation: a fluid dynamics study with laser Doppler anemometry.

PURPOSE: To study the influence of stent size and location on flow patterns in a physiological carotid model. METHODS: Wallstents were positioned in silicon models of the carotid artery at various locations: 2 stents appropriately sized to the anatomy were placed in (1) the internal carotid artery (ICA) and (2) the ICA extending completely into the common carotid artery so as to cover the external carotid artery (ECA) orifice. Another 2 stents were placed in the ICA extending (1) partially and (2) completely into the bulb to simulate stent displacement and disproportion between stent size and the original vessel geometry. Measurements were performed with laser Doppler anemometry (LDA) using pulsatile flow conditions (Reynolds number=250; flow 0.431 L/min; ICA:ECA flow rate ratio 70:30) in hemodynamically relevant cross sections. The hemodynamic changes were analyzed with 1-dimensional flow profiles. RESULTS: With the stent in the ICA, no changes of the normal flow profile were seen. For stents positioned in the ICA and extending partially or completely into the carotid bulb, the flow behavior was affected by the resistance of the stent to flow in the ECA. Hemodynamically relevant disturbances were seen in the ICA and ECA, especially in the separation zones (regions along the walls just after a bifurcation, bend, or curve). The ICA:ECA flow rate ratios shifted from 70:30 to 71.3:28.7 and from 70:30 to 75.1:24.9, respectively, in the 2 malpositioned stent models. With the stent placed in the ICA extending completely into the CCA, the ICA:ECA flow rate ratio shifted from 70:30 to 72.4:27.6. In this configuration, there were no notable flow changes in the ICA, but a clear diminishing of the separation zones in the ECA separation zones. CONCLUSIONS: Anatomically correct positioning of appropriately sized stents does not lead to relevant flow disturbances in the ICA. In the ECA, depending on the position, size, and interstices of the stent, the physiological flow was considerably disturbed when any part of the stent covered the inflow of the vessel. Disturbances were seen when the stent was positioned into the bulb. For clinical application, stent location and size must be carefully determined so that the stent covers the bifurcation completely or is in the ICA only.

Solid-phase synthesis of 7-acylamino-1,4-benzodiazepine-2,5-diones.

A method for the synthesis of polymer-bound 7-acylamino-benzodiazepine-2,5-diones is described. The amino group of an alpha-amino acid is linked to polystyrene or TentaGel resin via reductive amination of polymer-bound 4-alkoxy-2,6-dimethoxybenzaldehyde. Acylation with unprotected 5-nitroanthranilic acid is followed by base-catalyzed ring closure. Reduction of the nitro group yields enantiomerically pure 7-aminobenzodiazepin-2,5-dione attached via the N-4 atom to the resin. Acylation of the amino group on the aromatic ring with acid chlorides in N-methylpyrrolidone (no DMF, no base!) followed by cleavage from the resin using TFA/Me(2)S/water (90:5:5) provides the acylated benzodiazepinones in 52-69% (PS resin) and 41-48% (TG resin) yield (based on the theoretical loading) and >70% purity (HPLC, 210 nm). Using Fmoc-protected tyrosine fluoride in NMP gives the amino acid-coupled benzodiazepinones in 24% (PS resin) and 31% (TG resin) yield.

Microwave-assisted Pd(0)-catalyzed amination of aryl halides on solid support.

In this study, the microwave-assisted Pd(0)-catalyzed coupling of aryl halides to Rink resins is compared to a conventional heating protocol. While yields and purities of the coupling products were comparable under both conditions, microwave heating allows a significant acceleration of the reaction. The coupling of electron-deficient aryl halides proceeded within 10-15 minutes, while under conventional conditions 20 h of heating were necessary for complete conversion.

Palladium-catalyzed amination of aryl halides on solid support.

[reaction: see text] The first examples of the Pd(0)-catalyzed amination of aryl halides using Rink-resins as nitrogen source are described. Pd(2)dba(3)/BINAP/NaO-t-Bu was found to be the most efficient catalyst/base system, while a solvent mixture of dioxane and tert-butyl alcohol was shown to enhance the selectivity toward the desired monoarylation. Moderate to good yields and excellent purities of the amination products were found with electron-poor aryl halides, while electon-rich aryl halides failed to react under these conditions.