RESUMO
Glucose homeostasis is a vital and complex process, and its disruption can cause hyperglycaemia and type II diabetes mellitus. Glucokinase (GK), a key enzyme that regulates glucose homeostasis, converts glucose to glucose-6-phosphate in pancreatic ß-cells, liver hepatocytes, specific hypothalamic neurons, and gut enterocytes. In hepatocytes, GK regulates glucose uptake and glycogen synthesis, suppresses glucose production, and is subject to the endogenous inhibitor GK regulatory protein (GKRP). During fasting, GKRP binds, inactivates and sequesters GK in the nucleus, which removes GK from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. Compounds that directly hyperactivate GK (GK activators) lower blood glucose levels and are being evaluated clinically as potential therapeutics for the treatment of type II diabetes mellitus. However, initial reports indicate that an increased risk of hypoglycaemia is associated with some GK activators. To mitigate the risk of hypoglycaemia, we sought to increase GK activity by blocking GKRP. Here we describe the identification of two potent small-molecule GK-GKRP disruptors (AMG-1694 and AMG-3969) that normalized blood glucose levels in several rodent models of diabetes. These compounds potently reversed the inhibitory effect of GKRP on GK activity and promoted GK translocation both in vitro (isolated hepatocytes) and in vivo (liver). A co-crystal structure of full-length human GKRP in complex with AMG-1694 revealed a previously unknown binding pocket in GKRP distinct from that of the phosphofructose-binding site. Furthermore, with AMG-1694 and AMG-3969 (but not GK activators), blood glucose lowering was restricted to diabetic and not normoglycaemic animals. These findings exploit a new cellular mechanism for lowering blood glucose levels with reduced potential for hypoglycaemic risk in patients with type II diabetes mellitus.
Assuntos
Proteínas de Transporte/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal , Animais , Glicemia/metabolismo , Proteínas de Transporte/metabolismo , Núcleo Celular/enzimologia , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/enzimologia , Modelos Animais de Doenças , Hepatócitos , Humanos , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Hiperglicemia/enzimologia , Hipoglicemiantes/química , Fígado/citologia , Fígado/enzimologia , Fígado/metabolismo , Masculino , Modelos Moleculares , Especificidade de Órgãos , Fosforilação/efeitos dos fármacos , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Ligação Proteica/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Wistar , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêuticoRESUMO
We report the discovery of a novel series of 2-(3-alkoxy-1-azetidinyl) quinolines as potent and selective PDE10A inhibitors. Structure-activity studies improved the solubility (pH 7.4) and maintained high PDE10A activity compared to initial lead compound 3, with select compounds demonstrating good oral bioavailability. X-ray crystallographic studies revealed two distinct binding modes to the catalytic site of the PDE10A enzyme. An ex vivo receptor occupancy assay in rats demonstrated that this series of compounds covered the target within the striatum.
Assuntos
Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Quinolinas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Quinolinas/síntese química , Quinolinas/química , Solubilidade , Relação Estrutura-AtividadeRESUMO
We report the discovery of a novel series of biaryl ethers as potent and selective PDE10A inhibitors. Structure-activity studies improved the potency and decreased Pgp-mediated efflux found in the initial compound 4. X-ray crystallographic studies revealed two novel binding modes to the catalytic site of the PDE10A enzyme.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Descoberta de Drogas , Éteres/metabolismo , Éteres/farmacologia , Inibidores de Fosfodiesterase/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Éteres/síntese química , Éteres/química , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Relação Estrutura-AtividadeRESUMO
Structure-activity relationship (SAR) investigations of a novel class of triazolopyridazinone p38α mitogen activated protein kinase (MAPK) inhibitors are disclosed. From these studies, increased in vitro potency was observed for 2,6-disubstituted phenyl moieties and N-ethyl triazolopyridazinone cores due to key contacts with Leu108, Ala157 and Val38. Further investigation led to the identification of three compounds, 3g, 3j and 3m that are highly potent inhibitors of LPS-induced MAPKAP kinase 2 (MK2) phosphorylation in 50% human whole blood (hWB), and possess desirable in vivo pharmacokinetic and kinase selectivity profiles.
Assuntos
Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/farmacologia , Triazóis/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridazinas/síntese química , Piridazinas/química , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
We report the discovery of 6,7-dimethoxy-4-(pyridin-3-yl)cinnolines as novel inhibitors of phosphodiesterase 10A (PDE10A). Systematic examination and analyses of structure-activity-relationships resulted in single digit nM potency against PDE10A. X-ray co-crystal structure revealed the mode of binding in the enzyme's catalytic domain and the source of selectivity against other PDEs. High in vivo clearance in rats was addressed with the help of metabolite identification (ID) studies. These findings combined resulted in compound 39, a promising potent inhibitor of PDE10A with good in vivo metabolic stability in rats and efficacy in a rodent behavioral model.
Assuntos
Cumarínicos/síntese química , Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/metabolismo , Psicotrópicos/síntese química , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação , Cumarínicos/farmacologia , Descoberta de Drogas , Humanos , Modelos Moleculares , Inibidores de Fosfodiesterase/administração & dosagem , Ligação Proteica , Psicotrópicos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A novel class of pyrazolopyridazine p38alpha mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC(50) values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38alpha inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38alpha/beta over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of ca. 0.08mg/kg.
Assuntos
Anti-Inflamatórios/química , Benzamidas/química , Inibidores de Proteínas Quinases/química , Pirazóis/química , Piridazinas/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Benzamidas/síntese química , Benzamidas/farmacocinética , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Interleucina-8 , Lipopolissacarídeos/toxicidade , Masculino , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/síntese química , Pirazóis/farmacocinética , Piridazinas/síntese química , Piridazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
A novel class of fused pyrazole-derived inhibitors of p38alpha mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC(50) values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10 m and 10 q. Inhibitor 10 m was found to be efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of 0.1mg/kg while 10 q was found to have an ED(50) of 0.05-0.07 mg/kg.
Assuntos
Anti-Inflamatórios/química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Pirazóis/química , Piridonas/química , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Sítios de Ligação , Linhagem Celular , Simulação por Computador , Cristalografia por Raios X , Humanos , Interleucina-8/sangue , Lipopolissacarídeos/farmacologia , Masculino , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Piridonas/administração & dosagem , Piridonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The glucokinase-glucokinase regulatory protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure-activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK.
Assuntos
Aminopiridinas/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Glucoquinase/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Sulfonas/química , Aminopiridinas/química , Animais , Proteínas de Transporte/metabolismo , Cristalografia por Raios X , Glucoquinase/metabolismo , Glucose/metabolismo , Hipoglicemiantes/química , Fígado/citologia , Fígado/metabolismo , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Sulfonas/farmacologiaRESUMO
The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK-GKRP disrupters are revealed. Diarylmethanesulfonamide hit 6 (hGK-hGKRP IC50 = 1.2 µM) was optimized to lead compound 32 (AMG-0696; hGK-hGKRP IC50 = 0.0038 µM). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (nN â σ*S-X) in 32 was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound 32 was shown to induce GK translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = -45%; 100 mg/kg po, 3 h). X-ray analyses of 32 and several precursors bound to GKRP were also obtained. This novel disrupter of GK-GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Glucoquinase/metabolismo , Hipoglicemiantes/química , Sulfonamidas/química , Tiofenos/química , Transporte Ativo do Núcleo Celular , Animais , Glicemia/metabolismo , Núcleo Celular/metabolismo , Cristalografia por Raios X , Citoplasma/metabolismo , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Tiofenos/farmacocinética , Tiofenos/farmacologiaRESUMO
We report the discovery of novel imidazo[4,5-b]pyridines as potent and selective inhibitors of PDE10A. The investigation began with our recently disclosed ketobenzimidazole 1, which exhibited single digit nanomolar PDE10A activity but poor oral bioavailability. To improve oral bioavailability, we turned to novel scaffold imidazo[4,5-b]pyridine 2, which not only retained nanomolar PDE10A activity but was also devoid of the morpholine metabolic liability. Structure-activity relationship studies were conducted systematically to examine how various regions of the molecule impacted potency. X-ray cocrystal structures of compounds 7 and 24 in human PDE10A helped to elucidate the key bonding interactions. Five of the most potent and structurally diverse imidazo[4,5-b]pyridines (4, 7, 12b, 24a, and 24b) with PDE10A IC50 values ranging from 0.8 to 6.7 nM were advanced into receptor occupancy studies. Four of them (4, 12b, 24a, and 24b) achieved 55-74% RO at 10 mg/kg po.
RESUMO
Structure-activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N'-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the glucokinase-glucokinase regulatory protein (GK-GKRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 ("shelf region") as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50=0.005 µM and EC50=0.205 µM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly reduced blood glucose levels up to 6 h postdose.
Assuntos
Proteínas de Transporte/antagonistas & inibidores , Glucoquinase/antagonistas & inibidores , Glucoquinase/metabolismo , Piperazinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Glucoquinase/química , Humanos , Modelos Moleculares , Conformação Molecular , Piperazinas/síntese química , Piperazinas/química , Ligação Proteica/efeitos dos fármacos , Piridinas/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide 25 (AMG-1694). When dosed in ZDF rats, 25 showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally, hypoglycemia was not observed in either the hyperglycemic or normal rats.
Assuntos
Proteínas de Transporte/metabolismo , Glucoquinase/metabolismo , Hipoglicemiantes/química , Piperazinas/química , Animais , Sítios de Ligação , Proteínas de Transporte/química , Cristalografia por Raios X , Glucoquinase/química , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Piperazinas/efeitos adversos , Piperazinas/farmacologia , Conformação Proteica , Transporte Proteico , Ratos , Ratos Zucker , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/efeitos adversos , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
We report the identification of a PDE10A clinical candidate by optimizing potency and in vivo efficacy of promising keto-benzimidazole leads 1 and 2. Significant increase in biochemical potency was observed when the saturated rings on morpholine 1 and N-acetyl piperazine 2 were changed by a single atom to tetrahydropyran 3 and N-acetyl piperidine 5. A second single atom modification from pyrazines 3 and 5 to pyridines 4 and 6 improved the inhibitory activity of 4 but not 6. In the in vivo LC-MS/MS target occupancy (TO) study at 10 mg/kg, 3, 5, and 6 achieved 86-91% occupancy of PDE10A in the brain. Furthermore, both CNS TO and efficacy in PCP-LMA behavioral model were observed in a dose dependent manner. With superior in vivo TO, in vivo efficacy and in vivo PK profiles in multiple preclinical species, compound 5 (AMG 579) was advanced as our PDE10A clinical candidate.
Assuntos
Antipsicóticos/química , Benzimidazóis/química , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/metabolismo , Pirazinas/química , Administração Oral , Animais , Antipsicóticos/síntese química , Antipsicóticos/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Disponibilidade Biológica , Encéfalo/metabolismo , Cães , Humanos , Masculino , Atividade Motora/efeitos dos fármacos , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/química , Primatas , Conformação Proteica , Pirazinas/síntese química , Pirazinas/farmacologia , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
We have recently reported a novel approach to increase cytosolic glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, glucokinase regulatory protein (GKRP). These initial investigations culminated in the identification of 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK-GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lowered fed blood glucose levels (up to 58%).
Assuntos
Proteínas de Transporte/antagonistas & inibidores , Diabetes Mellitus/tratamento farmacológico , Glucoquinase/antagonistas & inibidores , Hepatócitos/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Piperazinas/química , Sulfonamidas/farmacologia , Animais , Disponibilidade Biológica , Glicemia/metabolismo , Proteínas de Transporte/metabolismo , Cristalografia por Raios X , Diabetes Mellitus/metabolismo , Modelos Animais de Doenças , Glucoquinase/metabolismo , Hepatócitos/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Piperazinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
In the previous report , we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (27, AMG-3969). When administered to db/db mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels.
Assuntos
Proteínas de Transporte/metabolismo , Glucoquinase/metabolismo , Hipoglicemiantes/química , Piperazinas/síntese química , Sulfonamidas/síntese química , Alcinos/síntese química , Alcinos/farmacocinética , Alcinos/farmacologia , Animais , Glicemia/metabolismo , Proteínas de Transporte/química , Glucoquinase/química , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Morfolinas/síntese química , Morfolinas/farmacocinética , Morfolinas/farmacologia , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ligação Proteica , Transporte Proteico , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologiaRESUMO
Our development of PDE10A inhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and poor metabolic stability. On the basis of cocrystal structure of 1 in human PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal structure of 26 in PDE10A confirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto-benzimidazole 34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.
Assuntos
Benzimidazóis/farmacologia , Desenho de Fármacos , Cetonas/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Animais , Benzimidazóis/administração & dosagem , Benzimidazóis/síntese química , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Cetonas/administração & dosagem , Cetonas/síntese química , Masculino , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/síntese química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , SuínosRESUMO
The p38alpha mitogen-activated protein (MAP) kinase is a central signaling molecule in many proinflammatory pathways, regulating the cellular response to a multitude of external stimuli including heat, ultraviolet radiation, osmotic shock, and a variety of cytokines especially interleukin-1beta and tumor necrosis factor alpha. Thus, inhibitors of this enzyme are postulated to have significant therapeutic potential for the treatment of rheumatoid arthritis, inflammatory bowel disease, and Crohn's disease, as well as other diseases where aberrant cytokine signaling is the driver of disease. In this communication, we describe a novel class of 7-alkyl-1,5-bis-aryl-pyrazolopyridinone-based p38alpha inhibitors. In particular, compound 3f is highly potent in the enzyme and cell-based assays, selective in an Ambit kinase screen, and efficacious (ED(50) < or = 0.01 mg/kg) in the rat collagen induced arthritis (CIA) model.