Quinazolin-4-piperidin-4-methyl sulfamide PC-1 inhibitors: alleviating hERG interactions through structure based design.
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.
Pfizer Global Research and Development, Cambridge Laboratories, Cambridge, MA 02139, USA.
Snahel D
SD
Patel
Wendy M
WM
Habeski
Alan C
AC
Cheng
Elisa
E
de la Cruz
Christine
C
Loh
Natasha M
NM
Kablaoui
D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D008133:Long QT Syndrome; D010003:Osteoarthritis / Q000188:drug therapy; D010727:Phosphoric Diester Hydrolases; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D010880:Piperidines; D011799:Quinazolines; D013449:Sulfonamides; C032727:piperidine; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases