RESUMO
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.
Assuntos
Quinases relacionadas a CDC2 e CDC28/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/farmacologia , Proteína Quinase CDC2/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 2 Dependente de Ciclina , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Encéfalo/metabolismo , Piperazinas/síntese química , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Barreira Hematoencefálica , Cães , Conformação Molecular , Permeabilidade , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ratos , Antagonistas da Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Isoquinolinas/síntese química , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Agonistas do Receptor de Serotonina/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Química Encefálica , Isoquinolinas/farmacocinética , Isoquinolinas/farmacologia , Ligantes , Ratos , Receptor 5-HT1A de Serotonina , Receptor 5-HT1B de Serotonina , Receptor 5-HT1D de Serotonina , Antagonistas da Serotonina/farmacocinética , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacocinética , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
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.