RESUMO
In this paper we report on observations of unusual linear defects forming spontaneously in polar free-standing smectic-C* films near the temperatures of thinning transitions. At high temperature a periodic structure of defects becomes the ground state of the system. We found that the defects are characterized by continuous rotation of the molecular orientation with a change of the sense of the rotation across the defects. We develop a simple theoretical model that describes the observed behavior. The structure of the defects is governed by the competition between two-dimensional quadratic and linear orientational elasticity. The proposed model explains the origin of the linear defects, the periodic structure and their transformation with temperature and chirality of the liquid crystal.
RESUMO
A series of N-propyl-8-chloro-6-substituted isoquinolones was identified as positive allosteric modulators of metabotropic glutamate receptor 2 (mGluR2 PAM) via high throughput screening (HTS). The subsequent synthesis and initial SAR exploration that led to the identification of compound 28 is described.
Assuntos
Piridinas/síntese química , Quinolonas/química , Receptores de Glutamato Metabotrópico/química , Regulação Alostérica , Ensaios de Triagem em Larga Escala , Humanos , Microssomos Hepáticos/metabolismo , Piridinas/química , Piridinas/farmacologia , Quinolonas/síntese química , Quinolonas/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
The discovery and characterization of compound 48, a selective and in vivo active mGlu2 receptor positive allosteric modulator (PAM), are described. A key to the discovery was the rational exploration of the initial HTS hit 13 guided by an overlay model built with reported mGlu2 receptor PAM chemotypes. The initial weak in vitro activity of the hit 13 was quickly improved, although compounds still had suboptimal druglike properties. Subsequent modulation of the physicochemical properties resulted in compounds having a more balanced profile, combining good potency and in vivo pharmacokinetic properties. Final refinement by addressing cardiovascular safety liabilities led to the discovery of compound 48. Besides good potency, selectivity, and ADME properties, compound 48 displayed robust in vivo activity in a sleep-wake electroencephalogram (sw-EEG) assay consistent with mGlu2 receptor activation, in accordance with previous work from our laboratories.
Assuntos
Nitrilas/síntese química , Piridonas/síntese química , Receptores de Glutamato Metabotrópico/agonistas , Regulação Alostérica , Animais , Encéfalo/metabolismo , Sinergismo Farmacológico , Canal de Potássio ERG1 , Eletroencefalografia , Canais de Potássio Éter-A-Go-Go/fisiologia , Células HEK293 , Humanos , Isomerismo , Camundongos , Nitrilas/farmacocinética , Nitrilas/farmacologia , Técnicas de Patch-Clamp , Piridonas/farmacocinética , Piridonas/farmacologia , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Sono REM/efeitos dos fármacos , Relação Estrutura-Atividade , VigíliaRESUMO
A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice.
Assuntos
Aminoácidos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Piridinas/farmacologia , Piridonas/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Sulfonamidas/farmacologia , Regulação Alostérica , Aminoácidos/química , Animais , Compostos Bicíclicos com Pontes/química , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Agonistas de Aminoácidos Excitatórios/química , Agonistas de Aminoácidos Excitatórios/classificação , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Piridinas/química , Piridonas/química , Piridonas/classificação , Piridonas/isolamento & purificação , Proteínas Recombinantes/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
In a previous study, the iodate-sulfite proton autoactivated reaction (Landolt reaction) was shown to exhibit spatial bistability and spatiotemporal oscillations when operated in an open spatial reactor with fixed "thickness", i.e., feed boundary to core distance. Here, we show that the spatial reactors with conical geometry enable one to rapidly probe the sensitivity of the above phenomena over a large range of the "thickness" parameter. This often-neglected parameter in chemical pattern studies plays an important role on the selection and stability of states. We reveal that the quenching capacity of slow diffusing polyacrylate ions on the spatiotemporal oscillations depends on this "thickness". The presented results should be useful for further research on reaction diffusion patterns and chemomechanical structures.
RESUMO
A new class of MMP-12 inhibitors was discovered and optimized using structure-based drug design methods. Modeling studies using a known MMP-12 crystal structure identified a new interaction mode for these new MMP-12 inhibitors. Further optimization resulted in the discovery of a compound displaying nanomolar activity against MMP-12 and which was co-crystallized with MMP-12.