RESUMO
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.
Assuntos
Piperidinas/farmacologia , Pirofosfatases/antagonistas & inibidores , Quinazolinas/farmacologia , Sulfonamidas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/química , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Síndrome do QT Longo , Osteoartrite/tratamento farmacológico , Diester Fosfórico Hidrolases , Piperidinas/química , Ligação Proteica , Quinazolinas/química , Sulfonamidas/químicaRESUMO
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.
