4-(Pyrrolidinyl)methoxybenzoic Acid Derivatives as a Potent, Orally Active VLA-4 Antagonist

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A novel series of benzoic acid derivatives as VLA-4 antagonists were synthesized. Optimization, focusing on activity and lipophilicity needed for cell permeability, resulted in the identification of 15b and 15e with good activity (IC₅₀=1.6 nM each) and moderate lipophilicity (Log D=2.0, 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30 mg/kg.