Discovery of N-{N-[(3-Cyanophenyl)sulfonyl]-4(R)-cyclobutylamino-(l)-prolyl}-4-[(3′,5′-dichloroisonicotinoyl)amino]-( 详细信息    查看全文

• 作者：Linus S. Lin ; Thomas Lanza ; ; James P. Jewell ; Ping Liu ; Carrie Jones ; Gerard R. Kieczykowski ; Kelly Treonze ; Qian Si ; Salony Manior ; Gloria Koo ; Xinchun Tong ; Junying Wang ; Anne Schuelke ; James Pivni
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：June 11, 2009
• 年：2009
• 卷：52
• 期：11
• 页码：3449-3452
• 全文大小：117K
• 年卷期：v.52,no.11(June 11, 2009)
• ISSN：1520-4804

文摘

Extremely potent very late antigen-4 (VLA-4) antagonists with picomolar, whole blood activity and slow dissociation rates were discovered by incorporating an amino substituent on the proline fragment of the initial lead structure. This level of potency against the unactivated form of VLA-4 was shown to be sufficient to overcome the poor pharmacokinetic profiles typical of this class of VLA-4 antagonists, and sustained activity as measured by receptor occupancy was achieved in preclinical species after oral dosing.