RESUMEN
Starting from the potent and selective but poorly brain penetrant 5-HT6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog.
Asunto(s)
Encéfalo/metabolismo , Piperazinas/síntesis química , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Barrera Hematoencefálica , Perros , Conformación Molecular , Permeabilidad , Piperazinas/farmacocinética , Piperazinas/farmacología , Ratas , Antagonistas de la Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
The protein structure guided design of a series of pyrazolo[1,5-a]pyrimidines with high potency for human cyclin-dependent kinase 2 (CDK2) is described. Some examples were shown to inhibit the growth of human colon tumour cells, were equipotent for CDK1 and were selective against GSK-3beta and other kinases.
Asunto(s)
Quinasas CDC2-CDC28/antagonistas & inhibidores , Pirimidinas/química , Pirimidinas/farmacología , Proteína Quinasa CDC2/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
The novel 8-piperazinyl-2,3-dihydropyrroloisoquinoline template was synthesized in nine steps. The template was N-substituted to give a series of compounds showing binding to human cloned 5-HT1A, 5-HT1B and 5-HT1D receptors with pKi's greater than 9 and selectivities up to 1000-fold against other serotonin, dopamine and adrenergic receptors. Several compounds were shown to possess weak partial agonist activity in cloned receptors, which translated to antagonism in in vitro studies.
Asunto(s)
Isoquinolinas/síntesis química , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Agonistas de Receptores de Serotonina/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Química Encefálica , Isoquinolinas/farmacocinética , Isoquinolinas/farmacología , Ligandos , Ratas , Receptor de Serotonina 5-HT1A , Receptor de Serotonina 5-HT1B , Receptor de Serotonina 5-HT1D , Antagonistas de la Serotonina/farmacocinética , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacocinética , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
Rational structure-based drug design has been applied to the antibiotic thiostrepton, in an attempt to overcome some of its' limitations. The identification of a proposed binding fragment allowed construction of a number of key fragments, which were derivatised to generate a library of potential antibiotics. These were then evaluated to determine their ability to bind to the L11 binding domain of the prokaryotic ribosome and inhibit bacterial protein translation.