RESUMO
Two syntheses of 3-substituted-4-amino-[3,2-c]thienopyridines have been developed to replace the standard literature route to these compounds, which uses unattractive conditions involving azide and high temperatures. The first synthesis utilizes a Friedel-Crafts reaction as its key ring-forming step, whereas the second route relies on an unprecedented intramolecular reductive cyclization between a nitroolefin and a nitrile as its key ring-forming step. The development and optimization of each 3-substituted-4-amino-[3,2-c]thienopyridine synthesis is discussed and a comparison of the routes is presented.
Assuntos
Piridinas/síntese química , Dióxido de Carbono/química , Ciclização , Halogênios/química , Metais/química , Oxirredução , Piridinas/química , Tiofenos/químicaRESUMO
A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.
Assuntos
Fármacos Antiobesidade/síntese química , Cicloeptanos/síntese química , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Hipolipemiantes/síntese química , Cetoácidos/síntese química , Ureia/análogos & derivados , Ureia/síntese química , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacocinética , Compostos de Bifenilo/farmacologia , Cicloeptanos/farmacocinética , Cicloeptanos/farmacologia , Diacilglicerol O-Aciltransferase/genética , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Cetoácidos/farmacocinética , Cetoácidos/farmacologia , Fígado/metabolismo , Camundongos , Camundongos Mutantes , Estereoisomerismo , Relação Estrutura-Atividade , Triglicerídeos/metabolismo , Ureia/farmacocinética , Ureia/farmacologia , Redução de PesoRESUMO
The optimization of potent MCHr1 antagonist 1 with respect to improving its in vitro profile by replacement of the 3,4-methylenedioxy phenyl (piperonyl) moiety led to the discovery of 19, a compound that showed excellent MCHr1 binding and functional potencies in addition to possessing superior hERG separation, CYP3A4 profile, and receptor cross-reactivity profiles.
Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Alquilação , Animais , Fenômenos Químicos , Físico-Química , Cromonas , Reações Cruzadas , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Relação Dose-Resposta a Droga , Canal de Potássio ERG1 , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Canais de Potássio Éter-A-Go-Go/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Humanos , Camundongos , Relação Estrutura-AtividadeRESUMO
The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.
Assuntos
Cromonas/síntese química , Cromonas/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Depressores do Apetite/farmacologia , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Dieta , Gorduras na Dieta , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Fenfluramina/farmacologia , Indicadores e Reagentes , Camundongos , Conformação Molecular , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of potent 2-carboxychromone-based melanin-concentrating hormone receptor 1 (MCHr1) antagonists were synthesized and evaluated for hERG (human Ether-a-go-go Related Gene) channel affinity and functional blockade. Basic dialkylamine-terminated analogs were found to weakly bind the hERG channel and provided marked improvement in a functional patch-clamp assay versus previously reported antagonists of the series.
Assuntos
Amidas/farmacologia , Cromonas/farmacologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Obesidade/tratamento farmacológico , Técnicas de Patch-Clamp , FarmacocinéticaRESUMO
A series of urea-based N-1-(2-aminoethyl)-indazoles was synthesized and evaluated for melanin-concentrating hormone receptor 1 (MCHr1) antagonism in both binding and functional assays. Several compounds that acted as MCHr1 antagonists were identified, and optimization afforded a compound with excellent binding affinity, good functional potency, and oral efficacy in a chronic model for weight loss in diet-induced obese mice.
Assuntos
Indazóis/síntese química , Indazóis/farmacologia , Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Ureia/química , Animais , Indazóis/química , Indazóis/uso terapêutico , Camundongos , Relação Estrutura-AtividadeRESUMO
The synthesis and biological evaluation of novel 3-amino indazole melanin concentrating hormone receptor-1 antagonists are reported, several of which demonstrated functional activity of less than 100nM. Compounds 19 and 28, two of the more potent compounds identified in this study, were characterized by high exposure in the brain and demonstrated robust efficacy when dosed in diet-induced obese mice.