Quinazolin-4-piperidin-4-methyl sulfamide PC-1 inhibitors: Alleviating hERG interactions through structure based design

详细信息    查看全文

• 作者：Snahel D. Patel ; Wendy M. Habeski ; Alan C. Cheng ; Elisa de la Cruz ; Christine Loh ; Natasha M. Kablaoui
• 关键词：PC-1 inhibitor ; hERG ; Homology model
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2009
• 出版时间：15 June 2009
• 年：2009
• 卷：19
• 期：12
• 页码：3339-3343
• 全文大小：869 K

文摘

PC-1 (NPP-1) inhibitors may be useful as therapeutics for the treatment of CDDP (calcium pyrophosphate dehydrate) deposition disease and osteoarthritis. We have identified a series of potent quinazolin-4-piperidin-4-ethyl sulfamide PC-1 inhibitors. The series, however, suffers from high affinity binding to hERG potassium channels, which can cause drug-induced QT prolongation. We used a hERG homology model to identify potential key interactions between our compounds and hERG, and the information gained was used to design and prepare a series of quinazolin-4-piperidin-4-methyl sulfamides that retain PC-1 activity but lack binding affinity for hERG.