Benzenesulfonamide indole inhibitors of cytosolic phospholipase A2α: Optimization of in vitro potency and rat pharmacokinetics for oral efficacy

The synthesis and structure–activity relationship of a series of benzenesulfonamide indole inhibitors of cPLA2α are described. Substitution of the benzenesulfonamide led to analogues with 50-fold improvement in potency versus the unsubstituted benzenesulfonamide lead compound. Rat pharmacokinetics in a minimal formulation was used to prioritize compounds, leading to the discovery of a potent inhibitor of cPLA2α with oral efficacy in models of rat carrageenan paw edema and Ascaris suum airway challenge in naturally sensitized sheep.

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