Bioisosteric replacement of anilide with benzoxazole: potent and orally bioavailable antagonists of VLA-4 |
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Authors: | Lin Linus S Lanza Thomas J Castonguay Laurie A Kamenecka Theodore McCauley Ermenegilda Van Riper Gail Egger Linda A Mumford Richard A Tong Xinchun MacCoss Malcolm Schmidt John A Hagmann William K |
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Institution: | Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. linus_lin@merck.com |
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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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