Novel multi-functional drugs for the treatment of inflammatory conditions

Several pathological conditions are accompanied by an imbalance of pro- and anti-inflammatory cytokines in plasma and tissues. These conditions include, among others, rheumatoid arthritis, ulcerative colitis, acute liver failure, non-alcoholic fatty liver disease, and acute lung disease (ALS). We prepared a series of N-substituted indoline derivatives that display potent antioxidant and anti-inflammatory activities and are readily solubilized in aqueous media as their corresponding acid addition salts. In a model of acute liver damage induced by LPS/D-galactosamine injection in mice, the compound 3-(indolin-1-yl)-N-isopropylpropan-1-amine dihydrochloride (code named AN-1284), reduced plasma alanine transferase (ALT), TNF-α and liver cell damage by 50-75% and mortality from 90% to 20% when injected sc in doses of 0.25-0.75 mg/kg of the salt. In a pilot experiment in mice with liver damage induced by 3 months of feeding with a high fat, low choline diet, AN-1284 (1 mg/kg/day), given for 3 weeks, significantly reduced plasma ALT, liver/body weight ratio and liver fat content. We established an LC-MS/MS method that was sensitive enough to measure AN-1284 and its major metabolite 3-(1H-indol-1-yl)-N-isopropylpropan-1-amine (code named AN-1422), in plasma and tissues after administration of AN-1284 in low doses.