PMC

X-ray crystal structure of 5 with JNK1.

4 lowered kidney p-c-jun at 8 h in the TNF-α challenge model in rat. 75 mg/kg po in MBP formulation. *p < 0.05 relative to TNF-α alone.

Structures and properties of 1–5, showing mean values from at least two experiments. HK-2 EC₅₀: Cellular potency was determined by the ability of compounds to prevent TNFα-stimulated accumulation of phospho-c-jun in human proximal tubule (HK-2) cells; LYSA solubility measurement (acetonitrile/water, 70:30, at 25 °C).

Reagents and conditions: (a) N,O-hydroxylamine hydrochloride, benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate, rt, 93%; (b) 3.0 M MeMgCl in THF, 0 °C, 72%; (c) aniline, dl-10-camphorsulfonic acid, 1,4-dioxane, 80 °C, 36%; (d) methyl-4-formylbenzoate, 25 wt % NaOMe in MeOH, rt, 95%; (e) 10% Pd/C, H₂, EtOAc, CH₂Cl₂, rt, 81%; (f) methyl 2-chloro-2-oxoacetate, toluene, 130 °C, used without further purification; (g) K₂CO₃, MeOH, 85 °C; (h) EDC-HCl, HOBT, DIPEA, CH₂Cl₂, rt, 12–82%.