RESUMO
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
Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.
Assuntos
Benzoxazinas/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina , Animais , Benzoxazinas/farmacologia , Disponibilidade Biológica , Encéfalo/metabolismo , Linhagem Celular , Estabilidade de Medicamentos , Humanos , Ensaio Radioligante , Ratos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-Atividade , Sinaptossomos/metabolismoRESUMO
Small molecule inhibitors have proven extremely useful for investigating signal transduction pathways and have the potential for development into therapeutics for inhibiting signal transduction pathways whose activities contribute to human diseases. Transforming growth factor beta (TGF-beta) is a member of a large family of pleiotropic cytokines that are involved in many biological processes, including growth control, differentiation, migration, cell survival, adhesion, and specification of developmental fate, in both normal and diseased states. TGF-beta superfamily members signal through a receptor complex comprising a type II and type I receptor, both serine/threonine kinases. Here, we characterize a small molecule inhibitor (SB-431542) that was identified as an inhibitor of activin receptor-like kinase (ALK)5 (the TGF-beta type I receptor). We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7, which are very highly related to ALK5 in their kinase domains. It has no effect on the other, more divergent ALK family members that recognize bone morphogenetic proteins (BMPs). Consistent with this, we demonstrate that SB-431542 is a selective inhibitor of endogenous activin and TGF-beta signaling but has no effect on BMP signaling. To demonstrate the specificity of SB-431542, we tested its effect on several other signal transduction pathways whose activities depend on the concerted activation of multiple kinases. SB-431542 has no effect on components of the ERK, JNK, or p38 MAP kinase pathways or on components of the signaling pathways activated in response to serum.
Assuntos
Receptores de Ativinas Tipo I/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Proteínas , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Transcrição Gênica/efeitos dos fármacos , Células 3T3 , Fator 2 Ativador da Transcrição , Ativinas/farmacologia , Animais , Proteína Morfogenética Óssea 4 , Proteínas Morfogenéticas Ósseas/farmacologia , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas de Ligação a DNA/metabolismo , Interações Medicamentosas , Ativação Enzimática , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Pressão Osmótica/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases , Ratos , Receptor do Fator de Crescimento Transformador beta Tipo I , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
Screening of our internal compound collection for inhibitors of the transforming growth factor beta1 (TGF-beta1) type I receptor (ALK5) identified several hits. Optimization of the dihydropyrroloimidazole hit 2 by introduction of a 2-pyridine and 3,4-methylenedioxyphenyl group gave 7, a selective ALK5 inhibitor. With this information, optimization of the triarylimidazole hit 8 gave the selective inhibitor 14, which inhibits TGF-beta1-induced fibronectin mRNA formation while displaying no measurable cytotoxicity in the 48 h XTT assay.
