RESUMO
In excitable cells, mitochondria play a key role in the regulation of the cytosolic Ca2+ levels. A dysregulation of the mitochondrial Ca2+ buffering machinery derives in serious pathologies, where neurodegenerative diseases highlight. Since the mitochondrial Na+/Ca2+ exchanger (NCLX) is the principal efflux pathway of Ca2+ to the cytosol, drugs capable of blocking NCLX have been proposed to act as neuroprotectants in neuronal damage scenarios exacerbated by Ca2+ overload. In our search of optimized NCLX blockers with augmented drug-likeness, we herein describe the synthesis and pharmacological characterization of new benzothiazepines analogues to the first-in-class NCLX blocker CGP37157 and its further derivative ITH12575, synthesized by our research group. As a result, we found two new compounds with an increased neuroprotective activity, neuronal Ca2+ regulatory activity and improved drug-likeness and pharmacokinetic properties, such as clog p or brain permeability, measured by PAMPA experiments.
Assuntos
Doenças Neurodegenerativas/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores , Acidente Vascular Cerebral/tratamento farmacológico , Tiazepinas , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Mitocôndrias , Neurônios/patologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Ratos , Tiazepinas/síntese química , Tiazepinas/farmacologiaRESUMO
The synthesis, biological evaluation, and molecular modeling of new 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides(4), 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide (6), and some hexahydropyrimido[5,4-c]quinoline-2,5-diones (9) produced earlier by our laboratory, as AChE/BuChE inhibitors, is described. From these analyses compound 4c resulted equipotent regarding the inhibition of cholinesterases'; inhibitors 6k, 9a, 9b were selective for AChE, whereas product 4d proved selective for BuChE. Docking analysis has been carry out in order to identify the binding mode in the active site, and to explain the observed selectivities. Only compound 9a has been shown to decrease K(+)-induced calcium signals in bovine chromaffin cells.
Assuntos
Canais de Cálcio/metabolismo , Colinesterases/metabolismo , Hidrazinas/síntese química , Hidrazinas/farmacologia , Modelos Moleculares , Quinolinas/síntese química , Quinolinas/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/química , Domínio Catalítico , Bovinos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Colinesterases/química , Desenho de Fármacos , Electrophorus , Hidrazinas/química , Quinolinas/químicaRESUMO
The systematic development of drugs is not new. This is shown by Withering's endeavour, 200 years ago, to make a useful therapeutic agent out of the digitalis plant. Today the way from idea to drug is long, taking about 10 to 15 years, and very expensive. A selection of approaches to drug discovery is described and illustrated with a practical example, the development of isradipine. In this example emphasis is placed on tissue selectivity, which even today remains an interesting research problem. One of the theories, suited to explain tissue selectivity, is also exposed.