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.
Subject(s)
Piperidines/pharmacology , Pyrophosphatases/antagonists & inhibitors , Quinazolines/pharmacology , Sulfonamides/pharmacology , Drug Design , Enzyme Inhibitors/chemistry , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Long QT Syndrome , Osteoarthritis/drug therapy , Phosphoric Diester Hydrolases , Piperidines/chemistry , Protein Binding , Quinazolines/chemistry , Sulfonamides/chemistryABSTRACT
The discovery of the CNS-penetrant and selective alpha(2C) adrenergic receptor antagonist N-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-[1,4]diazepan-1-yl]-ethyl}-2-phenoxy-nicotinamide, 13 is described. Structure-activity studies demonstrate the structural requirements for binding affinity, functional activity, and selectivity over other alpha(2)-AR subtypes.