RESUMO
The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.
Assuntos
Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/farmacologia , Receptores Purinérgicos P2X7/efeitos dos fármacos , Animais , Disponibilidade Biológica , Humanos , Antagonistas do Receptor Purinérgico P2X/farmacocinéticaRESUMO
Development of a scalable synthesis of an oxazine class of ß-secretase inhibitor is described. Trifluoromethylated acyloin synthesis by the reaction of a mandelic acid with trifluoroacetic anhydride in the presence of pyridine (Dakin-West reaction) was used as an efficient strategy to install the key trifluoromethyl substituent on the oxazine ring. Diastereoselective addition of methyl magnesium bromide to a cyclic sulfamidate imine and trimethylsilyl trifluoromethanesulfonate catalyzed intramolecular amidine formation to yield oxazine-3-amine are some of the significant, novel synthetic methods developed in this synthesis. These critical transformations allowed a concise 11-step route to the target compound with excellent overall yields.
RESUMO
Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.
Assuntos
Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Indóis/síntese química , Indóis/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Animais , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Indicadores e Reagentes , Indóis/farmacocinética , Isomerismo , Modelos Moleculares , Ratos , Relação Estrutura-Atividade , Tiofenos/farmacocinéticaRESUMO
A series of CCK2R-selective anthranilic amides is shown to derive CCK1R affinity via selective substitution of the amide side chain. Thus, extending the length of the original benzamide side chain by a single methylene unit imparts CCK1R affinity to the series, and further fine tuning of the affinity results in CCK1R selectivity of greater than 100-fold.
Assuntos
Isoxazóis/química , Receptor de Colecistocinina A/antagonistas & inibidores , Receptor de Colecistocinina B/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Benzamidas/farmacologia , Clonagem Molecular , Avaliação Pré-Clínica de Medicamentos , Genótipo , Aprendizagem em Labirinto , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Receptor de Colecistocinina A/genética , Receptor de Colecistocinina A/metabolismo , Receptor de Colecistocinina B/genética , Receptor de Colecistocinina B/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of cholecystokinin-2 receptor (CCK-2R) antagonists has been identified, as exemplified by anthranilic sulfonamide 1 (pK(i)=7.6). Pharmacokinetic and stability studies indicated that this series of compounds suffered from metabolic degradation, and that both the benzothiadiazole and piperidine rings were rapidly oxidized by liver enzymes. A combination of synthesis, computational methods, (1)H NMR conformational studies, and X-ray crystallographic analyses were applied to elucidate key pharmacophore elements, and to discover analogs with improved pharmacokinetic profiles, and high receptor binding affinity and selectivity.
Assuntos
Receptor de Colecistocinina B/antagonistas & inibidores , Animais , Benzotiazóis/síntese química , Benzotiazóis/química , Benzotiazóis/farmacologia , Cristalografia por Raios X , Humanos , Espectroscopia de Ressonância Magnética , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Receptor de Colecistocinina A/metabolismo , Receptor de Colecistocinina B/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
A novel strategy for the synthesis of cholecystokinin-2 receptor ligands was developed. The route employs a solution-phase synthesis of a series of anthranilic sulfonamides followed by a resin capture purification strategy to produce multi-milligram quantities of compounds for bioassay. The synthesis was used to produce >100 compounds containing various functional groups, highlighting the general applicability of this strategy and to address specific metabolism issues in our CCK-2 program.
Assuntos
Colecistocinina/metabolismo , Técnicas de Química Combinatória , Receptor de Colecistocinina B/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/farmacologia , Animais , Desenho de Fármacos , Humanos , Ligantes , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , ortoaminobenzoatos/químicaRESUMO
We have previously reported a novel class of tetrahydroindazoles that display potency against a variety of Gram-positive and Gram-negative bacteria, potentially via interaction with type II bacterial topoisomerases. Herein are reported SAR investigations of this new series. Several compounds possessing broad-spectrum potency were prepared. Further, these compounds exhibit activity against multidrug-resistant Gram-positive microorganisms equivalent to that against susceptible strains.
Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Indazóis/farmacologia , Inibidores da Topoisomerase II , Antibacterianos/síntese química , Antibacterianos/química , Desenho de Fármacos , Resistência a Múltiplos Medicamentos/fisiologia , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
A high throughput screening approach to the identification of selective cholecystokinin-2 receptor (CCK-2R) ligands resulted in the discovery of a novel series of antagonists, represented by 1-[2-[(2,1,3-benzothiadiazol-4-ylsulfonyl)amino]-5-chlorobenzoyl]-piperidine (1; CCK-2R, pK(I) = 6.4). Preliminary exploration of the structure-activity relationships around the anthranilic ring and the amide and sulfonamide moieties led to a nearly 50-fold improvement of receptor affinity and showed a greater than 1000-fold selectivity over the related cholecystokinin-1 receptor. Pharmacokinetic evaluation led to the identification of 4-[4-iodo-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-morpholine, 26d, a compound that demonstrates promising pharmacokinetic properties in the rat and dog with respect to plasma clearance and oral bioavailability and is a potent inhibitor in vivo of pentagastrin-stimulated acid secretion in the rat when dosed orally.