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Design of a new class of potent anti-inflammatory compounds-sterolides

Although inhaled steroids are the most effective therapy known for asthma, their use over long periods is associated by a number of severe side effects like growth retardation, suppression of hypothalamic-pituitary-adrenal axis (HPA), osteoporosis etc. Several strategies have been employed in development of anti-inflammatory steroids with reduced systemic side effects. Two main approaches have been: 1) increase of corticosteroids lipophilicity by esterifying the steroid hydroxyl groups, and 2) incorporation of metabolically labile functional groups at various positions of corticosteroids which undergo a predictable biotransformation to inactive metabolites upon entry into systemic circulation ("antedrug" or "soft" drug concept). We used a novel "sterolide" concept (steroid-macrolide conjugates1-3) where we combined property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells (peripheral blood mononuclear cells, peritoneal and alveolar macrophages) with potent anti-inflammatory activity of classic steroids. These molecules accumulate in macrophage cell line Raw264.7 and lymphoid cell line Jurkat in vitro with greatly prolonged efflux time. Such sterolide molecules show excellent anti-inflammatory activity in several animal models with little or no systemic effects otherwise seen with standard steroids. Lead molecule is currently in the late preclinical development stage.

sterolides; antiinflammatory; asthma

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