RESUMEN
Quinazolinones 8 and pyrido[3,4-d]pyrimidin-4-ones 9 as orally active and specific matrix metalloproteinase-13 inhibitors were discovered for the treatment of osteoarthritis. Starting from a high-through-put screening (HTS) hit thizolopyrimidin-dione 7, we obtained two chemotypes, 8 and 9, using computer-aided drug design (CADD) and methodical structure-activity relationship (SAR) studies. They occupy the unique S 1'-specificity pocket and do not bind to the Zn(2+) ion. Some pyrido[3,4-d]pyrimidin-4-ones, such as 10a, possess favorable absorption, distribution, metabolism, and elimination (ADME) and safety profiles. 10a effectively prevents cartilage damage in rabbit animal models of osteoarthritis without inducing musculoskeletal side effects when given at extremely high doses to rats.
Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Osteoartritis/tratamiento farmacológico , Piridinas/síntesis química , Pirimidinas/síntesis química , Quinazolinonas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Masculino , Piridinas/farmacocinética , Piridinas/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Quinazolinonas/farmacocinética , Quinazolinonas/farmacología , Conejos , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Ring-cleaved pleuromutilin derivatives comprised of a [5.3.1] bicyclic core structure have been synthesized and evaluated in vitro as antibacterial agents. Four of the compounds described were found to have MICsAsunto(s)
Antibacterianos/síntesis química
, Antibacterianos/química
, Antibacterianos/farmacología
, Diterpenos/síntesis química
, Diterpenos/química
, Diterpenos/farmacología
, Pruebas de Sensibilidad Microbiana
, Compuestos Policíclicos
, Staphylococcus aureus/efectos de los fármacos
, Streptococcus pneumoniae/efectos de los fármacos
, Relación Estructura-Actividad
, Pleuromutilinas
RESUMEN
The identification of a potent series of IKK-beta selective inhibitors based on an imidazothienopyrazine template and the oral efficacy of one such analog (22j) in the LPS-induced TNF-alpha release mouse model are described.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Quinasa I-kappa B/antagonistas & inhibidores , Pirazinas/química , Pirazinas/farmacología , Animales , Células Cultivadas , Inhibidores Enzimáticos/síntesis química , Humanos , Ratones , Pirazinas/síntesis química , Relación Estructura-ActividadRESUMEN
It has been hypothesized that peripherally restricted NMDA receptor antagonists may be effective analgesics for osteoarthritis pain. A class of novel quinoxalinedione atropisomers, first discovered for an NMDA receptor antagonist program for the treatment of stroke, was evaluated and further optimized with the goal of finding peripherally restricted NMDA receptor antagonists.