Bioisosteric replacement of anilide with benzoxazole: potent and orally bioavailable antagonists of VLA-4
| Autor: | Linus S. Lin, Thomas J. Lanza, John A. Schmidt, Richard A. Mumford, Xinchun Tong, Laurie A. Castonguay, Theodore M. Kamenecka, Linda A. Egger, Gail Van Riper, Malcolm MacCoss, William K. Hagmann, Ermenegilda McCauley |
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| Rok vydání: | 2003 |
| Předmět: |
Benzimidazole
Benzoxazoles Molecular model Hydrogen bond Stereochemistry Organic Chemistry Clinical Biochemistry Pharmaceutical Science Biological Availability Hydrogen Bonding Benzoxazole Integrin alpha4beta1 Biochemistry Chemical synthesis Rats chemistry.chemical_compound chemistry Drug Discovery Lipophilicity Molecular Medicine Peptide bond Animals Anilides Bioisostere Molecular Biology |
| Zdroj: | Bioorganicmedicinal chemistry letters. 14(9) |
| ISSN: | 0960-894X |
| Popis: | 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 α4β7. |
| Databáze: | OpenAIRE |
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