RESUMO
Two complementary stereospecific synthetic approaches for the preparation of unsymmetrical ortho-substituted N-(4,4-diphenylbut-3-enyl) derivatives of nipecotic acid are described. Determination of the activity of the prepared compounds at the GAT-1 transporter highlighted differing SAR requirements of the E- and Z-phenyl rings, and led to the discovery of a compound with comparable potency to tiagabine. Some attempts to replace nipecotic acid with alternative novel amino acids are also described.
Assuntos
Proteínas da Membrana Plasmática de Transporte de GABA/química , Inibidores da Captação de GABA/síntese química , Ácidos Nipecóticos/síntese química , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Inibidores da Captação de GABA/química , Inibidores da Captação de GABA/farmacologia , Ácidos Nipecóticos/química , Ácidos Nipecóticos/farmacologia , Ligação Proteica , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel imidazobenzazepine template (5a) with potent dual H(1)/5-HT(2A) antagonist activity was identified. Application of a zwitterionic approach to this poorly selective and poorly developable starting point successfully delivered a class of high quality leads, 3-[4-(3-R(1)-2-R-5H-imidazo[1,2-b][2]benzazepin-11-yl)-1-piperazinyl]-2,2-dimethylpropanoic acids (e.g., 9, 19, 20, and 21), characterized by potent and balanced H(1)/5-HT(2A) receptor antagonist activities and good developability profiles.
Assuntos
Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/uso terapêutico , Transtornos do Sono-Vigília/tratamento farmacológico , HumanosRESUMO
A novel series of trans-8-aminomethyl-1-oxa-3-azaspiro[4.5]decan-2-one derivatives was identified with potent NPY Y5 antagonist activity. Optimization of the original lead furnished compounds 23p and 23u, which combine sub-nanomolar Y5 activity with metabolic stability, oral bioavailability, brain penetration and strong preclinical profile for development. Both compounds significantly inhibited the food intake induced by a Y5 selective agonist with minimal effective doses of 3mg/kg po.
Assuntos
Carbamatos/química , Carbamatos/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/metabolismo , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Animais , Carbamatos/metabolismo , Carbamatos/farmacocinética , Linhagem Celular , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Ratos , Compostos de Espiro/metabolismo , Compostos de Espiro/farmacocinética , Relação Estrutura-AtividadeRESUMO
In an effort to identify selective drug like pan-antagonists of the 5-HT1 autoreceptors, studies were conducted to elaborate a previously reported dual acting 5-HT1 antagonist/SSRI structure. A novel series of compounds was identified showing low intrinsic activities and potent affinities across the 5-HT1A, 5-HT1B, and 5-HT1D receptors as well as high selectivity against the serotonin transporter. From among these compounds, 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (36) was found to combine potent in vivo activity with a strong preclinical developability profile, and on this basis it was selected as a drug candidate with the aim of assessing its potential as a fast-onset antidepressant/anxiolytic.
Assuntos
Imidazóis/farmacologia , Quinolinas/farmacologia , Antagonistas da Serotonina/farmacologia , Administração Oral , Animais , Células CHO , Cromatografia Líquida , Cricetulus , Descoberta de Drogas , Humanos , Imidazóis/administração & dosagem , Imidazóis/química , Espectroscopia de Ressonância Magnética , Masculino , Quinolinas/administração & dosagem , Quinolinas/química , Ratos Sprague-Dawley , Receptores de Serotonina/classificação , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/química , Espectrometria de Massas em TandemRESUMO
Bioisoteric replacement of the metabolically labile N-methyl amide group of a series of benzoxazinones with small heterocyclic rings has led to novel series of fused tricyclic benzoxazines which are potent 5-HT(1A/B/D) receptor antagonists with and without concomitant human serotonin transporter (hSerT) activity. Optimizing against multiple parameters in parallel identified 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045) as a potent 5-HT(1A/B/D) receptor antagonist with a high degree of selectivity over human ether-a-go-go related gene (hERG) potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models. On the basis of its outstanding overall profile, this compound was progressed as a clinical candidate with the ultimate aim to assess its potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden.
Assuntos
Ansiolíticos/síntese química , Antidepressivos/síntese química , Benzoxazinas/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina , Animais , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Antidepressivos/farmacocinética , Antidepressivos/farmacologia , Benzoxazinas/farmacocinética , Benzoxazinas/farmacologia , Callithrix , Linhagem Celular , Córtex Cerebral/metabolismo , Cricetinae , Cricetulus , Sistema Enzimático do Citocromo P-450/metabolismo , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Cobaias , Humanos , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Ligação Proteica , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , 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
The SAR of a new series of tetrahydrocarbazole derivatives is described: the appropriate decoration of this template led to the identification of a new class of NPY-1 antagonists showing good in vitro potency and a promising in vivo pharmacokinetic profile in rat.
Assuntos
Carbazóis , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Disponibilidade Biológica , Células CHO/efeitos dos fármacos , Carbazóis/síntese química , Carbazóis/química , Carbazóis/farmacologia , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Ratos , Receptores de Neuropeptídeo Y/química , Relação Estrutura-AtividadeRESUMO
Numerous analogues of the naturally occurring antibiotic althiomycin have been synthesised exploiting both total- and semi-synthetic methodologies. The antibacterial activity of these derivatives has been determined in whole cell assays and indicates the natural product exhibits a restricted SAR.