RESUMO
High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.
Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Pirimidinonas/química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Tiofenos/química , Administração Oral , Animais , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Pirimidinonas/síntese química , Pirimidinonas/uso terapêutico , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/uso terapêuticoRESUMO
A series of fused tricyclic mGluR1 antagonists containing a pyridone ring were synthesized. In vitro, these antagonists were potent against both human and rat isozymes, as well as selective for inhibiting mGluR1 over mGluR5. When dosed orally, several examples were active in vivo in a rat SNL test.
Assuntos
Piridonas/síntese química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Administração Oral , Analgésicos/farmacologia , Animais , Células Cultivadas , Ciclização , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Neuralgia/tratamento farmacológico , Ligação Proteica/efeitos dos fármacos , Piridonas/química , Piridonas/farmacologia , RatosRESUMO
A series of spiro-azetidines and azetidinones has been evaluated as novel blockers of the T-type calcium channel (Ca(V)3.2) which is a new therapeutic target for the potential treatment of both inflammatory and neuropathic pain. Confirmation and optimization of the potency, selectivity and DMPK properties of leads will be described.
Assuntos
Azetidinas/química , Bloqueadores dos Canais de Cálcio/síntese química , Canais de Cálcio Tipo T/química , Piperidinas/química , Compostos de Espiro/química , Animais , Azetidinas/síntese química , Azetidinas/uso terapêutico , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo T/metabolismo , Desenho de Fármacos , Humanos , Dor/tratamento farmacológico , Ligação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.
RESUMO
A key requirement of an autonomous self-replicating molecular machine, a protocell, is the ability to digest resources and turn them into building blocks. Thus a protocell needs a set of metabolic processes fueled by external free energy in the form of available chemical redox potential or light. We introduce and investigate a minimal photodriven metabolic system, which is based on photofragmentation of resource molecules catalyzed by genetic molecules. We represent and analyze the full metabolic set of reaction-kinetic equations and, through a set of approximations, simplify the reaction kinetics so that analytical expressions can be obtained for the building block production. The analytical approximations are compared with the full equation set and with corresponding experimental results to the extent they are available. It should be noted, however, that the proposed metabolic system has not been experimentally implemented, so this investigation is conducted to obtain a deeper understanding of its dynamics and perhaps to anticipate its limitations. We demonstrate that this type of minimal photodriven metabolic scheme is typically rate-limited by the front-end photoexcitation process, while its yield is determined by the genetic catalysis. We further predict that gene-catalyzed metabolic reactions can undergo evolutionary selection only for certain combinations of the involved reaction rates due to their intricate interactions. We finally discuss how the expected range of metabolic rates likely affects other key protocellular processes such as container growth and division as well as gene replication.
Assuntos
Evolução Biológica , Fenômenos Fisiológicos Celulares , Células/metabolismo , Luz , Modelos Biológicos , Fenômenos Fisiológicos Celulares/efeitos da radiação , Cinética , Oxirredução/efeitos da radiaçãoRESUMO
Properly substituted pyrazolo[1,5-a]pyrimidines are potent and selective CDK2 inhibitors. Compound 15j is orally available and showed efficacy in a mouse A2780 xenograft model.