Synthesis, characterization and pharmacological investigation of lysine and glycine conjugated amide prodrugs of (+)-ibuprofen

Abstract

(+)-ibuprofen [(+)-IBN] is a Non-steroidal anti inflammatory drug (NSAIDs) that is pharmacologically active stereoisomer of racemic form of ibuprofen. Literature showed that Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen and flubiprofen, are widely provide the protective effect against the neurodegenerative conditions. But the therapeutic application of NSAIDs in the CNS disorders were limited due to their limited brain distribution across the physiological barrier, blood brain barrier (BBB). BBB is composed of tightly connected endothelial cells of brain capillaries and the surrounding astrocytes and pericytes. The compounds which are able to cross the BBB by passive diffusion are small, lipophilic and uncharged at physiological PH . This study make an attempt to synthesize the derivatives (+)-IBN by conjugating with amino acids such as glycine and lysine that produced the two amide prodrugs, (+)-IBN-G and (+)-IBN-L. The objectives of this study are to synthesize the amide prodrugs of (+)-IBN with glycine and lysine produced (+)-IBN-G, (+)-IBN-L respectively and to perform detailed study on their physical and chemical properties, distribution profile in the brain, brain targeting efficiency parameters, pharmacological activities. The compounds synthesized will act as prodrugs of (+)-IBN and after the administration the (+)- IBN was released at the desired site by enzymatic or non-enzymatic hydrolysis and synthesized prodrugs showed the enhanced brain distribution, protective against neurodegeneration, enhanced anti inflammatory activity, reduction in the gastric side effect such as ulcer formation in the stomach.