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, 14 (9), 2331-4

Bioisosteric Replacement of Anilide With Benzoxazole: Potent and Orally Bioavailable Antagonists of VLA-4

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Bioisosteric Replacement of Anilide With Benzoxazole: Potent and Orally Bioavailable Antagonists of VLA-4

Linus S Lin et al. Bioorg Med Chem Lett.

Abstract

We have designed and synthesized a series of heterocyclic bioisosteres for an anilide based on molecular modeling. Excellent potency was retained in the benzoxazole and the benzimidazole derivatives, where a hydrogen bond acceptor is appropriately positioned to mimic the amide bond oxygen. The deletion of the hydrogen bond donor (N-H) led to improved lipophilicity and bioavailability. In the process, 9a was identified as a potent, specific, and bioavailable VLA-4 antagonist, while 9c was found to be a potent and bioavailable dual antagonist of VLA-4 and alpha(4)beta(7).

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