RESUMO
We report on the optimization of 4H-1,2,4-triazole derivatives to increase their activity and selectivity as glycine transporter 1 (GlyT1) inhibitors. Structure-activity relationship exploration resulted in the identification of a 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile (14u) compound with markedly higher selectivity for GlyT1. Physiochemical studies revealed that 14u exists as a stable pair of atropisomers under physiological conditions. We successfully separated the atropisomers to obtain active enantiomer (R)-14u, which displayed favorable pharmacokinetic properties, as well as positive results in the mice Y-maze test.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Triazóis/síntese química , Animais , Maleato de Dizocilpina/farmacologia , Feminino , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Triazóis/farmacologiaRESUMO
Optimization starting with our lead compound 1 (IC(50)=4.9 nM) led to the identification of pyrrolidinyl phenylurea derivatives. Further modification toward improvement of the bioavailability provided (R)-1-(1-((6-fluoronaphthalen-2-yl)methyl)pyrrolidin-3-yl)-3-(2-(2-hydroxyethoxy)phenyl)urea 32 (IC(50)=1.7 nM), a potent and orally active CCR3 antagonist.
Assuntos
Compostos de Fenilureia/química , Pirrolidinas/química , Receptores CCR3/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Meia-Vida , Macaca fascicularis , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacocinética , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Receptores CCR3/metabolismoRESUMO
The synthesis and structure-activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC(50)=190 nM) derived from initial screening hit compound 1 (IC(50)=600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC(50)=4.9 nM) as a potent CCR3 antagonist.
Assuntos
Receptores CCR3/antagonistas & inibidores , Ureia/análogos & derivados , Avaliação Pré-Clínica de Medicamentos , Humanos , Naftalenos/síntese química , Naftalenos/química , Naftalenos/metabolismo , Prolina/química , Ligação Proteica , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/metabolismo , Receptores CCR3/metabolismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/metabolismoRESUMO
We synthesized and evaluated the inhibitory activity of a series of 2-(1-alkylpiperidin-4-yl)-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]acetamide derivatives against T-type Ca(2+) channels. Structure-activity relationship studies revealed that the position of the amide structure was important for the potent inhibitory activity toward T-type Ca(2+) channels. In addition, the introduction of an appropriate substituent on the pendant benzene ring played a crucial role for the selectivity towards T-type Ca(2+) channels over L-type Ca(2+) channels and the potent bradycardic activity of these derivatives. Oral administration of N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-2-(1-{2-[2-(2-methoxyethoxy)phenyl]ethyl}piperidin-4-yl)acetamide (4f), which had superior selectivity for T-type Ca(2+) channels over L-type Ca(2+) channels, lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, which is often caused by traditional L-type Ca(2+) channel blockers.
Assuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Acetamidas/química , Animais , Anti-Hipertensivos/química , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Flúor/química , Masculino , Mibefradil/química , Mibefradil/farmacologia , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
To identify novel glycine transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure-activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.
Assuntos
Compostos de Bifenilo/síntese química , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Isoquinolinas/química , Isoquinolinas/síntese química , Triazóis/química , Animais , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Linhagem Celular , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Isoquinolinas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
We synthesized and evaluated inhibitory activity against T-type Ca(2+) channels for a series of 1-alkyl-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide derivatives. Structure-activity relationship studies have revealed that the isopropyl substituent at the benzylic position plays an important role in exerting potent inhibitory activity, and the absolute configuration of the benzylic position was found to be opposite that of mibefradil, which was first launched as a new class of T-type Ca(2+) channel blocker. Oral administration of N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-1-[2-(3-methoxyphenyl)ethyl]piperidine-4-carboxamide (17f) lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, an adverse effect often caused by traditional L-type Ca(2+) channel blockers.
Assuntos
Amidas/química , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Piperidinas/química , Amidas/farmacologia , Amidas/uso terapêutico , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo T/química , Canais de Cálcio Tipo T/metabolismo , Linhagem Celular , Cobaias , Humanos , Hipertensão/tratamento farmacológico , Masculino , Ratos , Ratos Endogâmicos SHR , Relação Estrutura-AtividadeRESUMO
Inhibitors of factor Xa (FXa), a crucial serine protease in the coagulation cascade, have attracted a great deal of attention as a target for developing antithrombotic agents. We previously reported findings from our optimization study of a high-throughput screening (HTS) derived lead compound 1a that resulted in the discovery of potent amidine-containing FXa inhibitors represented by compound 2. We also conducted an alternative optimization study of 1a without incorporating a strong basic amidine group, which generally has an adverse effect on the pharmacokinetic profile after oral administration. Replacement of 4-methoxybenzene with a 1,4-benzodiazepine structure and introduction of a hydroxy group at the central benzene led to the discovery of the potent and orally effective factor Xa inhibitor 14i (darexaban, YM150). Subsequent extensive study revealed a unique aspect to the pharmacokinetic profile of this compound, wherein the hydroxy moiety of 14i is rapidly transformed into its glucuronide conjugate 16 (YM-222714) as an active metabolite after oral administration and it plays a major role in expression of potent anticoagulant activity in plasma. The distinctive, potent activity of inhibitor 14i after oral dosing was explained by this unique pharmacokinetic profile and its favorable membrane permeability. Compound 14i is currently undergoing clinical development for prevention and treatment of thromboembolic diseases.
Assuntos
Azepinas/síntese química , Benzamidas/síntese química , Inibidores do Fator Xa , Fibrinolíticos/síntese química , Administração Oral , Animais , Anticoagulantes/síntese química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Azepinas/química , Azepinas/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Disponibilidade Biológica , Domínio Catalítico , Fator Xa/química , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Glucuronídeos/metabolismo , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Ratos , Ratos Endogâmicos F344 , Relação Estrutura-AtividadeRESUMO
We synthesized and evaluated inhibitory activity against T-type Ca(2+) channels for a series of 1-alkyl-N-[2-ethyl-2-(4-fluorophenyl)butyl]piperidine-4-carboxamide derivatives. Structure-activity relationship studies have revealed that dialkyl substituents at the benzylic position play an important role in increasing inhibitory activity. Oral administration of N-[2-ethyl-2-(4-fluorophenyl)butyl]-1-(2-phenylethyl)piperidine-4-carboxamide (20d) lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, which is often caused by traditional L-type Ca(2+) channel blockers.
Assuntos
Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacologia , Canais de Cálcio Tipo T/metabolismo , Piperidinas/farmacologia , Animais , Anti-Hipertensivos/química , Função do Átrio Direito/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Cobaias , Masculino , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Ratos , Ratos Endogâmicos SHR , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de TempoRESUMO
A series of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and their bradycardic activities were evaluated in isolated guinea pig right atria. Structure-activity relationship studies revealed that the introduction of an appropriate substituent and its position on the 1,2,3,4-tetrahydroisoquinoline ring are essential for potent in vitro activity. Furthermore, the tether between the piperidyl moiety and the terminal aromatic ring is important for potent antihypertensive activity. Oral administration of 6-fluoro-1-isopropyl-2-{[1-(2-phenylethyl)piperidin-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline (3b) to spontaneously hypertensive rats (SHR) elicited antihypertensive effects without inducing reflex tachycardia, which is often caused by traditional L-type Ca²âº channel blockers.
Assuntos
Anti-Hipertensivos/química , Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/uso terapêutico , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo T/metabolismo , Cobaias , Masculino , Ratos , Ratos Endogâmicos SHR , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/administração & dosagemRESUMO
We describe the preparation and evaluation of a novel series of glycine transporter 1 (GlyT1) inhibitors derived from a high-throughput screening hit. The SAR studies resulted in the discovery of 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (6p). A pharmacokinetic study was also conducted and revealed that 6p had excellent oral bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.
Assuntos
Compostos de Bifenilo/síntese química , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Nootrópicos/síntese química , Triazóis/síntese química , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Disponibilidade Biológica , Compostos de Bifenilo/farmacocinética , Compostos de Bifenilo/farmacologia , Encéfalo/metabolismo , Permeabilidade da Membrana Celular , Camundongos , Atividade Motora/efeitos dos fármacos , Nootrópicos/farmacocinética , Nootrópicos/farmacologia , Relação Estrutura-Atividade , Triazóis/farmacocinética , Triazóis/farmacologiaRESUMO
A series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene)acetamide derivatives were optimized to achieve potent agonistic activity, both in vitro and in vivo, for the arginine vasopressin V(2) receptor, resulting in the eventual discovery of compound 1g. Molecular modeling of compound 1g with V(2) receptor was also examined to evaluate the binding mode of this series of compounds.
Assuntos
Acetamidas/farmacologia , Arginina Vasopressina/farmacologia , Arginina/farmacologia , Receptores de Vasopressinas/agonistas , Acetamidas/síntese química , Animais , Arginina/metabolismo , Arginina Vasopressina/química , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Signal transducers and activators of transcription 6 (STAT6) is an important transcription factor in interleukin (IL)-4 signaling pathway and a key regulator of the type 2 helper T (Th2) cell immune response. Therefore, STAT6 may be an excellent therapeutic target for allergic conditions, including asthma and atopic diseases. Previously, we reported 4-aminopyrimidine-5-carboxamide derivatives as STAT6 inhibitors. To search for novel STAT6 inhibitors, we synthesized fused bicyclic pyrimidine derivatives and identified a 7H-pyrrolo[2,3-d]pyrimidine derivative as a STAT6 inhibitor. Optimization of the pyrrolopyrimidine derivatives led to identification of 2-[4-(4-{[7-(3,5-difluorobenzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}phenyl)piperazin-1-yl]acetamide (24, AS1810722) which showed potent STAT6 inhibition and a good CYP3A4 inhibition profile. Compound 24 also inhibited in vitro Th2 differentiation without affecting type 1 helper T (Th1) cell differentiation and eosinophil infiltration in an antigen-induced mouse asthmatic model after oral administration.
Assuntos
Pirimidinas/síntese química , Pirróis/síntese química , Fator de Transcrição STAT6/antagonistas & inibidores , Administração Oral , Animais , Asma/tratamento farmacológico , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Eosinófilos/efeitos dos fármacos , Humanos , Imunidade , Camundongos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Relação Estrutura-Atividade , Células Th2/efeitos dos fármacosRESUMO
Our laboratory has identified several acrylamide derivatives with potent CCR3 inhibitory activity. In the present study, we evaluated the in vitro metabolic stability (CL(int); mL/min/kg) of these compounds in human liver microsomes (HLMs), and assessed the relationship between their structures and CL(int) values. Among the compounds identified, N-{(3R)-1-[(6-fluoro-2-naphthyl)methyl]pyrrolidin-3-yl}-2-[1-(2-hydroxybenzoyl)piperidin-4-ylidene]acetamide (30j) was found to be a potent inhibitor (IC(50)=8.4nM) with a high metabolic stability against HLMs.
Assuntos
Acetamidas/síntese química , Acrilamidas/química , Antialérgicos/síntese química , Naftalenos/síntese química , Receptores CCR3/antagonistas & inibidores , Acetamidas/química , Acetamidas/farmacologia , Acrilamidas/síntese química , Acrilamidas/farmacocinética , Animais , Antialérgicos/química , Antialérgicos/farmacocinética , Haplorrinos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Naftalenos/química , Naftalenos/farmacologia , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Receptores CCR3/metabolismo , TermodinâmicaRESUMO
A series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetamide derivatives was synthesized, and their structure-activity relationships were examined in order to identify potent and selective arginine vasopressin V(2) receptor agonists. Attempts to substitute other chemical groups in place of the 2-pyridilmethyl moiety of 1a led to the discovery that potent V(2) binding affinity could be obtained with a wide range of functional groups. This structural tolerance allowed for the manipulation of other attributes, such as selectivity against V(1a) receptor affinity or avoidance of the undesirable inhibition of cytochrome P450 (CYP), without losing potent affinity for the V(2) receptor. Some representative compounds obtained in this study were also found to decrease urine volume in awake rats.
Assuntos
Arginina Vasopressina/metabolismo , Benzamidas/química , Benzamidas/farmacologia , Benzazepinas/química , Benzazepinas/farmacologia , Receptores de Vasopressinas/agonistas , Animais , Antidiuréticos/síntese química , Antidiuréticos/química , Antidiuréticos/farmacologia , Benzamidas/síntese química , Benzazepinas/síntese química , Células CHO , Cricetinae , Cricetulus , Humanos , Estrutura Molecular , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores de Vasopressinas/metabolismo , Relação Estrutura-AtividadeRESUMO
The present work describes the discovery of novel series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene)acetamide derivatives as arginine vasopressin (AVP) V(2) receptor agonists. By replacing the amide juncture in YM-35278 with a direct ring connection gave compound 10a, which acts as a V(2) receptor agonist. These studies provided the potent, orally active non-peptidic V(2) receptor agonists 10a and 10j.
Assuntos
Arginina Vasopressina/metabolismo , Benzazepinas/síntese química , Receptores de Vasopressinas/agonistas , Animais , Antidiuréticos/síntese química , Antidiuréticos/química , Antidiuréticos/farmacologia , Benzazepinas/química , Benzazepinas/farmacologia , Células CHO , Cricetinae , Cricetulus , Masculino , Estrutura Molecular , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores de Vasopressinas/metabolismo , Relação Estrutura-AtividadeRESUMO
As a result of the various N-bicyclo-5-chloro-1H-indole-2-carboxamide derivatives with a hydroxy moiety synthesized in an effort to discover novel glycogen phosphorylase (GP) inhibitors, 5-chloro-N-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-indole-2-carboxamide (5b) was found to have potent inhibitory activity. The introduction of fluorine atoms both at a position adjacent to the hydroxy group and in the central benzene moiety lead to the optically active derivative 5-chloro-N-[(5R)-1,3,6,6-tetrafluoro-5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1H-indole-2-carboxamide (25e(alpha), which was the most potent compound in this series (IC(50)=0.020microM). This compound inhibited glucagon-induced glucose output in cultured primary hepatocytes with an IC(50) value of 0.69microM, and showed oral hypoglycemic activity in diabetic db/db mice at 10mg/kg. Compound 25e(alpha) also had an excellent pharmacokinetic profile, with high oral bioavailability and a long plasma half-life, in male SD rats. The binding mode of 25e(alpha) to this molecule and the role of fluorine atoms in that binding were speculated in an enzyme docking study.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Inibidores Enzimáticos/síntese química , Glicogênio Fosforilase/antagonistas & inibidores , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Indóis/síntese química , Indóis/farmacologia , Administração Oral , Animais , Benzamidas/química , Células Cultivadas , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glucose , Hepatócitos/efeitos dos fármacos , Hipoglicemiantes/química , Indóis/química , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Obesos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
During our research using a high-throughput screening system for discovery of a new class of human liver glycogen phosphorylase a (hLGPa) inhibitors, a series of 3-(3,4-dichlorophenyl)acrylamide derivatives were synthesized, and their inhibitory activities toward hLGPa were evaluated. Among the derivatives, (2E,2'E)-N,N'-pentane-1,5-diylbis[3-(3,4-dichlorophenyl)acrylamide] (6c) inhibited hLGPa with an IC(50) value of 0.023 microM. An X-ray crystallographic study of the enzyme-6c complex showed that the inhibitor is bound at the dimer interface site, where the 3,4-dichlorophenyl moiety interacts hydrophobically with the enzyme.
Assuntos
Acrilamidas/farmacologia , Diclorofeno/farmacologia , Inibidores Enzimáticos/farmacologia , Glicogênio Fosforilase Hepática/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Acrilamidas/síntese química , Sítios de Ligação , Cristalografia por Raios X , Diclorofeno/síntese química , Inibidores Enzimáticos/síntese química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Hipoglicemiantes/síntese química , Solventes/química , Relação Estrutura-AtividadeRESUMO
In our previous study on discovering novel types of CCR3 antagonists, we found a fluoronaphthalene derivative (1) that exhibited potent CCR3 inhibitory activity with an IC(50) value of 20 nM. However, compound 1 also inhibited human cytochrome P450 2D6 (CYP2D6) with an IC(50) value of 400 nM. In order to reduce its CYP2D6 inhibitory activity, we performed further systematic structural modifications on 1. In particular, we focused on reducing the number of lipophilic moieties in the biphenyl part of 1, using ClogD(7.4) values as the reference index of lipophilicity. This research led to the identification of N-{(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-(piperidin-1-ylcarbonyl)isonicotinamide 1-oxide (30) which showed comparable CCR3 inhibitory activity (IC(50)=23 nM) with much reduced CYP2D6 inhibitory activity (IC(50)=29,000 nM) compared with 1.
Assuntos
Inibidores do Citocromo P-450 CYP2D6 , Desenho de Fármacos , Hidrocarbonetos Fluorados/farmacologia , Naftalenos/farmacologia , Receptores CCR3/antagonistas & inibidores , Cálcio/química , Cálcio/metabolismo , Citoplasma/química , Citoplasma/metabolismo , Humanos , Hidrocarbonetos Fluorados/síntese química , Concentração Inibidora 50 , Naftalenos/síntese química , Receptores CCR3/metabolismo , Relação Estrutura-AtividadeRESUMO
Signal transducers and activators of transcription 6 (STAT6) is a key regulator of the type 2 helper T (Th2) cell immune response and a potential therapeutic target for allergic diseases such as asthma and atopic diseases. To search for potent and orally bioavailable STAT6 inhibitors, we synthesized a series of 4-benzylaminopyrimidine-5-carboxamide derivatives and evaluated their STAT6 inhibitory activities. Among these compounds, 2-[(4-morpholin-4-ylphenyl)amino]-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide (25y, YM-341619, AS1617612) showed potent STAT6 inhibition with an IC(50) of 0.70nM, and also inhibited Th2 differentiation in mouse spleen T cells induced by interleukin (IL)-4 with an IC(50) of 0.28 nM without affecting type 1 helper T (Th1) cell differentiation induced by IL-12. In addition, compound 25y showed an oral bioavailability of 25% in mouse.
Assuntos
Morfolinas/administração & dosagem , Morfolinas/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Fator de Transcrição STAT6/antagonistas & inibidores , Administração Oral , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Fenômenos Químicos , Físico-Química , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Morfolinas/química , Morfolinas/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Fator de Transcrição STAT6/metabolismo , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismoRESUMO
A series of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives were prepared and evaluated as inhibitors of human liver glycogen phosphorylase a (hLGPa). One compound, 5-chloro-N-[4-(1,2-dihydroxyethyl)phenyl]-1H-indole-2-carboxamide (2f), inhibited hLGPa with an IC(50) of 0.90microM. The pyridine analogue of 2f showed inhibitory activity of glucagon-induced glucose output in cultured primary hepatocytes with an IC(50) of 0.62microM and oral hypoglycemic activity in diabetic db/db mice. Crystallographic determination of the complex of 2f with hLGPa showed binding of the inhibitor in a solvent cavity at the dimer interface, with the two hydroxyl groups making favorable electrostatic interactions with hLGPa.