Quinazolin-4-piperidin-4-methyl sulfamide PC-1 inhibitors: Alleviating hERG interactions through structure based design |
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Authors: | Snahel D Patel Wendy M Habeski Alan C Cheng Elisa de la Cruz Christine Loh Natasha M Kablaoui |
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Institution: | Pfizer Global Research and Development, Cambridge Laboratories, Cambridge, MA 02139, USA |
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Abstract: | 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. |
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