RESUMO
Protein-based drug discovery strategies have the distinct advantage of providing insights into the molecular mechanisms of chemical effectors. Currently, there are no known trehalose-6-phosphate phosphatase (TPP) inhibitors that possess reasonable inhibition constants and chemical scaffolds amenable to convenient modification. In the present study, we subjected recombinant TPPs to a two-tiered screening approach to evaluate several diverse compound groups with respect to their potential as TPP inhibitors. From a total of 5452 compounds tested, N-(phenylthio)phthalimide was identified as an inhibitor of nematode TPPs with apparent Ki values of 1.0 µM and 0.56 µM against the enzymes from the zoonotic roundworms Ancylostoma ceylanicum and Toxocara canis, respectively. Using site-directed mutagenesis, we demonstrate that this compound acts as a suicide inhibitor that conjugates a strictly conserved cysteine residue in the vicinity of the active site of nematode TPPs. The anthelmintic properties of N-(phenylthio)phthalimide were assessed in whole nematode assays using larvae of the ascaroids T. canis and T. cati, as well as the barber's pole worm Haemonchus contortus. The compound was particularly effective against each of the ascaroids with an IC50 value of 9.3 µM in the survival assay of T. cati larvae, whereas no bioactivity was observed against H. contortus.
Assuntos
Anti-Helmínticos/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas de Helminto/antagonistas & inibidores , Nematoides/enzimologia , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Ftalimidas/farmacologia , Animais , Proteínas de Helminto/metabolismo , Monoéster Fosfórico Hidrolases/metabolismoRESUMO
As it is getting increasingly difficult to achieve gains in the density and power efficiency of microelectronic computing devices because of lithographic techniques reaching fundamental physical limits, new approaches are required to maximize the benefits of distributed sensors, micro-robots or smart materials. Biologically-inspired devices, such as artificial neural networks, can process information with a high level of parallelism to efficiently solve difficult problems, even when implemented using conventional microelectronic technologies. We describe a mechanical device, which operates in a manner similar to artificial neural networks, to solve efficiently two difficult benchmark problems (computing the parity of a bit stream, and classifying spoken words). The device consists in a network of masses coupled by linear springs and attached to a substrate by non-linear springs, thus forming a network of anharmonic oscillators. As the masses can directly couple to forces applied on the device, this approach combines sensing and computing functions in a single power-efficient device with compact dimensions.
Assuntos
Processamento Eletrônico de Dados/métodos , Algoritmos , Processamento Eletrônico de Dados/instrumentação , Redes Neurais de Computação , Dinâmica não LinearRESUMO
Rho kinase is an important target implicated in a variety of cardiovascular diseases. Herein, we report the optimisation of the fragment derived ATP-competitive ROCK inhibitors 1 and 2 into lead compound 14A. The initial goal of improving ROCK-I potency relative to 1, whilst maintaining a good PK profile, was achieved through removal of the aminoisoquinoline basic centre. Lead 14A was equipotent against both ROCK-I and ROCK-II, showed good in vivo efficacy in the spontaneous hypertensive rat model, and was further optimised to demonstrate the scope for improving selectivity over PKA versus hydroxy Fasudil 3.
Assuntos
Aminas/química , Isoquinolinas/química , Piperidinas/química , Inibidores de Proteínas Quinases/química , Quinolonas/química , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Aminas/síntese química , Aminas/uso terapêutico , Animais , Modelos Animais de Doenças , Hipertensão/tratamento farmacológico , Modelos Químicos , Modelos Moleculares , Piperidinas/síntese química , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Quinolonas/síntese química , Quinolonas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismoRESUMO
Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo.
Assuntos
Amidas/química , Compostos Azabicíclicos/síntese química , Compostos Bicíclicos com Pontes/química , Indóis/síntese química , Piperazinas/química , Receptor CB1 de Canabinoide/agonistas , Animais , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Desenho de Fármacos , Humanos , Indóis/química , Indóis/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Piperazinas/síntese química , Piperazinas/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
Novel tricyclic indole-3-carboxamides were synthesized as structurally restricted analogs of bicyclic indoles, and found to be potent CB1 cannabinoid receptor agonists. The CB1 agonist activity depended on the absolute configuration of the chiral center of the tricyclic ring. The preferred enantiomer was more potent than the structurally unconstrained lead compound. Structure-activity relationships in the amide side chain of the indole C-3 position were also investigated.
Assuntos
Amidas/química , Indóis/química , Receptor CB1 de Canabinoide/agonistas , Amidas/síntese química , Amidas/farmacocinética , Animais , Desenho de Fármacos , Humanos , Camundongos , Microssomos/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
A study into the effect of reaction variables on the quaternization of REM resin-bound tertiary amines was undertaken. The influence of resin matrix, solvent, reaction time, temperature, and amount of quaternization agent on the outcome of reaction was evaluated by reaction monitoring using (19)F NMR. The highest yields of tertiary amine products were seen when DMSO was used as reaction solvent in conjunction with a reaction time of 18 h at room temperature. The use of heating for extended reaction times tended to depress yields, indicating product cleavage during quaternization. Quaternization on PS-DVB resin was found to be more robust than reaction on PS-PEG matrices where yields were generally considerably lower than the observed conversions. DMSO was the most efficient reaction solvent for both resins despite poor swelling of the quaternization starting material.