RESUMO
The therapeutic potential of monoacylglycerol lipase (MAGL) inhibitors in central nervous system-related diseases has attracted attention worldwide. However, the availability of reversible-type inhibitor is still limited to clarify the pharmacological effect. Herein, we report the discovery of novel spiro chemical series as potent and reversible MAGL inhibitors with a different binding mode to MAGL using Arg57 and His121. Starting from hit compound 1 and its co-crystal structure with MAGL, structure-based drug discovery (SBDD) approach enabled us to generate various spiro scaffolds like 2a (azetidine-lactam), 2b (cyclobutane-lactam), and 2d (cyclobutane-carbamate) as novel bioisosteres of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl moiety in 1 with higher lipophilic ligand efficiency (LLE). Optimization of the left hand side afforded 4f as a promising reversible MAGL inhibitor, which showed potent in vitro MAGL inhibitory activity (IC50 6.2 nM), good oral absorption, blood-brain barrier penetration, and significant pharmacodynamic changes (2-arachidonoylglycerol increase and arachidonic acid decrease) at 0.3-10 mg/kg, po. in mice.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Oxazinas/farmacologia , Compostos de Espiro/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Monoacilglicerol Lipases/metabolismo , Oxazinas/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
Monoacylglycerol lipase (MAGL) is a major serine hydrolase that hydrolyzes 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) and glycerol in the brain. Because 2-AG and AA are endogenous biologically active ligands in the brain, inhibition of MAGL is an attractive therapeutic target for CNS disorders, particularly neurodegenerative diseases. In this study, we report the structure-based drug design of novel piperazinyl pyrrolidin-2-ones starting from our hit compounds 2a and 2b. By enhancing the interaction of the piperazinyl pyrrolidin-2-one core and its substituents with the MAGL enzyme via design modifications, we identified a potent and reversible MAGL inhibitor, compound ( R)-3t. Oral administration of compound ( R)-3t to mice decreased AA levels and elevated 2-AG levels in the brain.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Piperazina/química , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Animais , Técnicas de Química Sintética , Inibidores Enzimáticos/química , Masculino , Camundongos , Modelos Moleculares , Monoacilglicerol Lipases/química , Conformação Proteica , Pirrolidinas/químicaRESUMO
The synthesis and biological evaluation of a series of novel 3-phenylpiperidine-4-carboxamide derivatives are described. These compounds are generated by hybridization of the substructures from two types of tachykinin NK(1) receptor antagonists. Compound 42 showed high metabolic stability and excellent efficacy in the guinea-pig GR-73637-induced locomotive activity assay at 1 and 24h after oral administration. It also exhibited good pharmacokinetic profiles in four animal species, and a low potential in a pregnane X receptor induction assay.
Assuntos
Amidas/química , Amidas/farmacologia , Citocromo P-450 CYP3A/metabolismo , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/química , Administração Oral , Amidas/síntese química , Amidas/farmacocinética , Animais , Ativação Enzimática/efeitos dos fármacos , Cobaias , Humanos , Microssomos/metabolismo , Atividade Motora/efeitos dos fármacos , Piperidinas/síntese química , Piperidinas/farmacocinética , Receptor de Pregnano X , Receptores da Neurocinina-1/metabolismo , Receptores de Esteroides/metabolismo , EstereoisomerismoRESUMO
As a novel class of IKKbeta inhibitors, a series of tricyclic furan derivatives was designed and synthesized based on the structure of known thiophene IKKbeta inhibitors. Among the various fused furan derivatives synthesized, a benzothieno[3,2-b]furan derivative 13a displayed potent inhibitory activity towards IKKbeta in enzymatic and cellular assays. The potent inhibitory activity originates from an intramolecular non-bonded S...O interaction which was confirmed by the X-ray structure of JNK3 with 16k. The introduction of further substituents on the core structure led to the discovery of the 6-alkoxy derivatives, which possessed a comparable IKKbeta inhibitory activity to 13a and an improved metabolic stability. Among these, appropriately lipophilic compounds 16a, h, i, and 13g (log D>2) were found to possess good oral bioavailability.