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Bioorg Med Chem Lett. 2004 May 3;14(9):2331-4.

Bioisosteric replacement of anilide with benzoxazole: potent and orally bioavailable antagonists of VLA-4.

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Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.


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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