RESUMO
A focused exploration targeting conformationally restricted analogues of Vestipitant, resulted in the discovery of novel, in vitro potent NK(1) antagonists. In particular, two of the compounds reported exhibited a good pharmacokinetic (PK) profile and produced anxiolytic-like effects in the gerbil foot tapping (GFT) in vivo model.
Assuntos
Ansiolíticos/síntese química , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/síntese química , Ansiolíticos/química , Ansiolíticos/farmacocinética , Desenho de Fármacos , Fluorbenzenos , Humanos , Conformação Molecular , Piperidinas/química , Piperidinas/farmacocinética , Receptores da Neurocinina-1/metabolismoRESUMO
GW196771 is a potent antagonist of the modulatory glycine site of the N-methyl-D-aspartate (NMDA) receptor exhibiting outstanding in vivo profile in different animal models of chronic pain. With the aim to maximize the drug delivery to the target organs a suitable "pro-drug approach" was attempted; in this regards two conjugates of GW196771 with nutrients actively transported into the brain, namely adenosine and glucose, were prepared and investigated. These compounds, were evaluated in vitro in terms of their stability in rat plasma and in vivo on rats. Although an improvement was observed in terms of brain penetration of the esters vs. the parent compound, the amount of the latter did not increase significantly, probably due to some degradation events in the brain, different from the expected ester hydrolysis, resulting in a reduced availability of GW196771.
Assuntos
Glicina/antagonistas & inibidores , Glicina/farmacologia , Indenos/metabolismo , Indenos/farmacologia , Pró-Fármacos/síntese química , Pirrolidinas/metabolismo , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Glicina/uso terapêutico , Indenos/uso terapêutico , Monossacarídeos/química , Monossacarídeos/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Pró-Fármacos/metabolismo , Pirrolidinas/química , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , Ratos , Receptores de N-Metil-D-Aspartato/uso terapêuticoRESUMO
A series of benzoazepine derivatives, bearing suitable substituents at the C-3 position, was designed and evaluated by superimposition with the pharmacophore model of the glycine binding site. To fully explore the SAR of this class of compounds and to allow the preparation of new different compounds at the C-3 position, appropriate synthetic routes were set up. The benzoazepines were evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-D-aspartate (NMDA) in mice. This further analysis confirmed the preliminary results previously reported and that compound 27 is the most promising compound (Ki=32 nM, ED(50)=0.09 mg/kg, i.v.) in this series. Significant neuroprotective effect was observed after both pre- and post-ischaemia administration in the MCAo model. In particular, after post-ischaemia administration, it was found to be still effective when the administration was delayed up to 6 h after occlusion of the middle cerebral artery.
Assuntos
Anticonvulsivantes/síntese química , Azepinas/síntese química , Fármacos Neuroprotetores/síntese química , Receptores de Glicina/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Arteriopatias Oclusivas/complicações , Azepinas/química , Azepinas/farmacologia , Sítios de Ligação , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Masculino , Camundongos , Artéria Cerebral Média , Modelos Moleculares , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
In an effort to discover novel druglike NK(1) receptor antagonists a new series of suitably substituted C-phenylpiperazine derivatives was identified by an appropriate chemical exploration of related N-phenylpiperazine analogues, with the specific aim to maximize their in vitro affinity and optimize in parallel their pharmacokinetic profile. Among the compounds synthesized, 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) was identified as one of the most in vitro potent and selective NK(1) receptor antagonists ever discovered, showing appropriate pharmacokinetic properties and in vivo activity. On the basis of its preclinical profile, this compound was selected as a drug candidate.
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Piperazinas/química , Piperidinas/farmacologia , Administração Oral , Animais , Células CHO , Cricetinae , Cricetulus , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Fluorbenzenos , Gerbillinae , Farmacocinética , Piperazinas/farmacologia , Piperidinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
Chiral tetrahydroquinoline derivatives have been prepared by an asymmetric Mannich-type condensation reaction using commercially available vinyloxyethylsilane and a N-arylimino R-(+)-t-butyl lactate ester, in the presence of a catalytic amount of metal triflates as Lewis acids. This synthetic approach gave rise to the target aldehyde intermediate in moderate facial diastereoselectivity and in high chemical yield. This efficient route enabled to scale up the synthesis of an orally bioavailable glycine antagonist showing outstanding in vivo anti-hyperalgesic activity in different animal models of sustained inflammation and chronic neuropathic pain.
Assuntos
Glicina/antagonistas & inibidores , Hidroquinonas/síntese química , Hidroquinonas/farmacologia , Hiperalgesia/tratamento farmacológico , Animais , Disponibilidade Biológica , Modelos Animais de Doenças , Hidroquinonas/farmacocinética , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis of a series of carbazole derivatives and their SAR at the NPY Y1 receptor is described. Modulation of physicochemical properties by appropriate decoration led to the identification of a high-affinity NPY Y1 antagonist that shows high brain penetration and modest oral bioavailability.
Assuntos
Carbazóis/síntese química , Carbazóis/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Carbazóis/farmacocinética , Fenômenos Químicos , Físico-Química , Cricetinae , Cricetulus , Meia-Vida , Indicadores e Reagentes , Masculino , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
To identify neuroprotective agents after stroke, new substituted tetrahydroquinoline derivatives were designed as antagonists of the glycine binding site associated to the NMDA receptor, satisfying the key pharmacophoric requirements. In particular, the racemate 3c exhibited outstanding in vivo activity in the MCAo model in rats, when given iv both pre- and post-ischemia. Pure enantiomers 3c-(+) and 3c-(-) have been prepared following an original synthetic route. Despite the significant difference of activity observed in vitro, they shown similar neuroprotective profile in the MCAo model in rats.