Abstract
Searching new targets for anti-inflammatory drug de sign, agents with the isoindole skeleton were focused on the basis of preliminary studies of NSAI Ds as COX-1 and/or COX-2 enzyme inhibitors. Thus several novel N-substituted isoindoline derivatives as possible bi ologically active compounds were prepared as analogues of Indoprofen ( 1) starting from cis -2-((4- methylphenyl)carbonyl)cyclohexanecarboxylic acid ( 3) by treatment with primary arylamines.
Highlights
IntroductionBehaviour and structural studies of several substituted or fused isoindole derivatives
We described preparation, behaviour and structural studies of several substituted or fused isoindole derivatives
These compounds could serve as scaffolds for potential Alzheimer’s disease (AD) diagnostic probes to monitor Aβ fibrils.3c The Indoprofen derivatives possess prostanoid EP4 receptor agonist properties and regulate inflammatory cytokines after an inflammatory stimulus.3d These results prompted us to prepare the optimized drug candidates 3-aryl substituted and partially saturated isoindolone derivatives, developing new potential anti-inflammatory drugs associated with lower gastrointestinal (GI) side-effects
Summary
Behaviour and structural studies of several substituted or fused isoindole derivatives. In a more recent study Indoprofen is reported to increase production of the survival of motor neurone protein, suggesting it may provide insight into treatments for spinal muscular atrophy.3a Ellies et al have found that Indoprofen and its derivatives promote bone growth.3b Based on the structural features of Indoprofen, a series of isoindol-1-one derivatives were designed and synthesized, and all showed very good binding affinities, with Ki values in the subnanomolar (nM) range against aggregated Aβ42 fibrils These compounds could serve as scaffolds for potential Alzheimer’s disease (AD) diagnostic probes to monitor Aβ fibrils.3c The Indoprofen derivatives possess prostanoid EP4 receptor agonist properties and regulate inflammatory cytokines after an inflammatory stimulus.3d These results prompted us to prepare the optimized drug candidates 3-aryl substituted and partially saturated isoindolone derivatives, developing new potential anti-inflammatory drugs associated with lower gastrointestinal (GI) side-effects (e.g. gastritis, peptic ulceration, gastric bleeding). According to a comparison of the structures of the non-selective Indoprofen (1) and the selective COX-2 inhibitor Celecoxib (2) below, some modifications were required to reduce the side-effects (with gastric tolerance and without cardiovascular risks) keeping the potent anti-inflammatory activity of the compounds (Figure 1)
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