RESUMO
Multiple lines of evidence suggest that Retinoic Acid Related Orphan Nuclear Receptor gamma t (RORγt) is a potent therapeutic target for inflammatory bowel disease (IBD). However, systemic blockade of RORγt easily leads to thymic lymphoma and aberrant liver function. Therefore, the development of gut-limited RORγt antagonists may lead to the development of innovative IBD therapeutics that improve safety and retain effectiveness. We discovered SPH7854, a potent and selective RORγt antagonist. The effect of SPH7854 on the differentiation of T helper 1 (Th1)/Th17/regulatory T (Treg) cells was evaluated in mouse and human primary cells. SPH7854 (2-(4-(ethylsulfonyl)phenyl)-N- (6-(2-methyl-2-(pyridin-2-yl) propanoyl)pyridin-3-yl)acetamide) dose-dependently inhibited interleukin-17A (IL-17A) secretion from mouse CD4 + T cells and human peripheral blood mononuclear cells (PBMC). Additionally, SPH7854 strongly suppressed Th17 cell differentiation and considerably promoted Treg cell differentiation while slightly affected Th1 cell differentiation from mouse CD4 + T cells. The pharmacokinetic (PK) studies indicated that SPH7854 was restricted to the gut: the bioavailability and maximal plasma concentration of SPH7854 after oral administration (6 mg/kg) were 1.24 ± 0.33 % and 4.92 ± 11.81 nM, respectively, in rats. Strikingly, oral administration of SPH7854 (5 mg/kg and 15 mg/kg) twice daily significantly alleviated 2, 4, 6-trinitrobenzensulfonic acid (TNBS)-induced colitis in rats. SPH7854, especially at 15 mg/kg, significantly alleviated symptoms and improved macroscopic signs and microscopic structure in rat colitis, with decreased colonic mucosal levels of IL-17A, IL-6, tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and myeloperoxidase (MPO). These evidences indicated that blockade of RORγt activity via a gut-limited antagonist may be an effective and safe therapeutic strategy for IBD treatment.
RESUMO
BACKGROUND: Obesity and metabolic syndrome (MetS) have been acknowledged to commonly co-exist and lead to increased risks of stroke, whereas the association between various BMI-based metabolic phenotypes and development of intracranial atherosclerotic stenosis (ICAS) remained controversial. METHODS: A total of 5355 participants were included from the Asymptomatic Polyvascular Abnormalities Community (APAC) study. Participants were categorized into six groups according to their body mass index (BMI) and MetS status. ICAS was assessed using transcranial Doppler (TCD) Ultrasonography. Logistic regression was employed to evaluate the association between BMI-based metabolic phenotypes and ICAS. RESULTS: 704 participants were diagnosed with ICAS. Compared to the metabolic healthy normal weight (MH-NW) group, the metabolic unhealthy normal weight (MUH-NW) group demonstrated a higher risk of ICAS (full-adjusted odds ratio [OR], 1.91; 95% confidence interval [CI], 1.42-2.57), while no significant association was observed in the metabolic unhealthy obesity (MUO) group (full-adjusted OR, 1.07; 95% CI, 0.70-1.65) and other metabolic healthy groups regardless of BMI. The results were consistent across gender, age, smoking, alcohol intake, and physical activity subgroups. CONCLUSION: The present study suggested that MUH-NW individuals had a significant association with increased risk of ICAS compared with MH-NW individuals.
Assuntos
Índice de Massa Corporal , Arteriosclerose Intracraniana , Síndrome Metabólica , Fenótipo , Humanos , Masculino , Feminino , Estudos Transversais , Pessoa de Meia-Idade , Arteriosclerose Intracraniana/epidemiologia , Prevalência , Síndrome Metabólica/epidemiologia , Idoso , Obesidade/epidemiologia , Obesidade/complicações , Fatores de Risco , Adulto , Ultrassonografia Doppler TranscranianaRESUMO
Janus kinases (JAKs) play a critical role in modulating the function and expression of inflammatory cytokines related to rheumatoid arthritis (RA). Herein, we report the design, synthesis, and structure-activity relationships (SARs) of a series of novel quinazoline derivatives as JAK inhibitors. Among these inhibitors, compound 11n showed high potency against JAKs (JAK1/JAK2/JAK3/TYK2, IC50 = 0.40, 0.83, 2.10, 1.95 nM), desirable metabolic characters, and excellent pharmacokinetic properties. In collagen-induced arthritis (CIA) models, compound 11n exhibited significant reduction in joint swelling with good safety, which could be served as a potential therapeutic candidate for the treatment of inflammatory diseases.
Assuntos
Artrite Reumatoide , Inibidores de Janus Quinases , Humanos , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Janus Quinases , Relação Estrutura-Atividade , Artrite Reumatoide/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
As a continuation study, 29 novel triazoles containing benzyloxy phenyl isoxazole side chain were designed and synthesized based on our previous work. The majority of the compounds exhibited high potency in vitro antifungal activities against eight pathogenic fungi. The most active compounds 13, 20 and 27 displayed outstanding antifungal activity with MIC values ranging from <0.008 µg/mL to 1 µg/mL, and showed potent activity against six drug-resistant Candida auris isolates. Growth curve assays further confirmed the high potency of these compounds. Moreover, compounds 13, 20 and 27 showed a potent inhibitory activity on biofilm formation of C. albicans SC5314 and C. neoformans H99. Notably, compound 13 showed no inhibition of human CYP1A2 and low inhibitory activity against CYP2D6 and CYP3A4, suggesting a low risk of drug-drug interactions. With high potency in vitro and in vivo and good safety profiles, compound 13 will be further investigated as a promising candidate.
Assuntos
Antifúngicos , Cryptococcus neoformans , Humanos , Antifúngicos/farmacologia , Antifúngicos/química , Triazóis/farmacologia , Triazóis/química , Isoxazóis , Relação Estrutura-Atividade , Candida albicans , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND: Serum albumin to globulin ratio (A/G) has been widely used as a representative biomarker for assessing inflammation and nutrition status. However, in patients with acute ischemic stroke (AIS), the predictive value of serum A/G has rarely been reported. We aimed to evaluate whether serum A/G is associated with prognosis in stroke. METHODS: We analyzed data from the Third China National Stroke Registry. The patients were categorized into quartile groups according to the serum A/G at admission. Clinical outcomes included poor functional outcomes (modified Rankin Scale [mRS] score of 3-6 or 2-6) and all-cause mortality at 3 months and1 year. Multivariable logistic regressions and Cox proportional hazards regressions were used to evaluate the association of serum A/G with the risk of poor functional outcomes and all-cause mortality. RESULTS: A total of 11, 298 patients were included in this study. After adjustment for confounding factors, patients in the highest serum A/G quartile had a lower proportion of mRS score 2-6 (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.76-1.00) and mRS score 3-6 (OR, 0.87; 95% CI, 0.73-1.03) at 3 months follow-up. At 1 year follow-up, there was a significant association between higher serum A/G and mRS score 3-6 (OR, 0.68; 95% CI, 0.57-0.81). We also found that the highest serum A/G was related to decreased risk of all-cause mortality (hazard ratio [HR], 0.58; 95% CI, 0.36-0.94) at 3 months follow-up. Similar results were found at 1-year follow-up. CONCLUSIONS: Lower serum A/G levels were associated with poor functional outcomes and all-cause mortality at 3 months and 1-year follow-up in patients with acute ischemic stroke.
Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , AVC Isquêmico/complicações , Albumina Sérica , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Prognóstico , Biomarcadores , Isquemia Encefálica/complicações , Fatores de RiscoRESUMO
The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure. Renin, the first and rate-limiting enzyme of the RAAS, is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. Therefore, various direct renin inhibitors (DRIs) have been researched over recent decades; however, most exhibited poor pharmacokinetics and oral bioavailability due to the peptidomimetic or nonpeptidomimetic structures with a molecular weight (MW) of >600, and only aliskiren is approved. This study introduces a novel class of DRIs comprised of a 2-carbamoyl morpholine scaffold. These compounds have a nonpeptidomimetic structure and a MW of <500. The representative compound 26 was highly potent despite not occupying S1'-S2' sites or the opened flap region used by other DRIs and exerted a significant antihypertensive efficacy via oral administration on double transgenic mice carrying both the human angiotensinogen and the human renin genes.
RESUMO
Renin is the rate-limiting enzyme in the renin-angiotensin-aldosterone system (RAAS) which regulates blood pressure and renal function and hence is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. However, the development of direct renin inhibitors (DRIs) with favorable oral bioavailability has been a longstanding challenge for many years. This problem was thought to be because most of the reported DRIs were peptide-like structures or nonpeptide-like structures with a molecular weight (MW) of > 600. Therefore, we tried to find nonpeptidomimetic DRIs with a MW of < 500 and discovered the promising 2-carbamoyl morpholine derivative 4. In our efforts to improve the pharmacokinetic profile of 4 without a significant increase in the MW, we discovered compound 18 (SPH3127), which demonstrated higher bioavailability and a more potent antihypertensive effect in preclinical models than aliskiren and has completed a phase II clinical trial for essential hypertension.
Assuntos
Hipertensão , Renina , Amidas/farmacologia , Amidas/uso terapêutico , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Fumaratos/farmacologia , Fumaratos/uso terapêutico , Humanos , Hipertensão/tratamento farmacológico , Morfolinas/farmacologia , Renina/farmacologia , Renina/uso terapêutico , Sistema Renina-AngiotensinaRESUMO
Small-molecule irreversible tyrosine kinase inhibitors as high potent agents have led to improvements in disease-free and overall survival in patients with HER2-amplified cancer. The approved irreversible HER2 inhibitors, neratinib and pyrotinib, both lack HER2 selectivity, leading to off-target adverse events in patients. The development of HER2 mutation during treatment also hampers the progress of the treatment. We used a molecular hybridization strategy for structural optimizations, in conjunction with in vitro and in vivo drug-like property screening, to obtain a clinical candidate SPH5030. Overall, SPH5030 showed excellent activities against four frequent kinds of HER2 mutants and high relative HER2 selectivity compared with neratinib and pyrotinib, good pharmacokinetic characteristics with desirable bioavailabilities, and significant in vivo antitumor efficacy in xenograft mouse models, especially in a HER2 mutation A775_G776insYVMA xenograft mouse model with its potency much higher than those of neratinib and pyrotinib.
Assuntos
Neoplasias da Mama , Receptor ErbB-2 , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos , Camundongos , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
PURPOSE: To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of single- and multiple-dose SPH3127 in healthy individuals. METHODS: This was a randomized, double-blind, placebo-controlled, Phase I dose-escalation study. FINDINGS: SPH3127 exposure, expressed as Cmax, AUC0-t, and AUC0-∞, was proportionally increased with dose for a range of 25-800 mg (single ascending dose [SAD]) and 100-400 mg daily (multiple ascending doses [MADs]). In an SAD, the Cmax values with 25, 50, 100, 200, 400, and 800 mg of SPH3127 were 90.67, 344.50, 523.50, 1239.50, 2445.00, and 5753.33 ng/mL, respectively. The corresponding AUC0-t values were 294.48, 843.62, 1109.33, 2858.56, 6697.50, and 13057.83 h × ng/mL. In MADs, after the first dose of SPH3127, the Cmax values with 100, 200, and 400 mg of SPH3127 were 421.50, 969.00, and 2468.33 ng/mL, respectively. The corresponding AUC0-t values were 1279.28, 2275.77, and 5934.26 h × ng/mL. At steady state, the Cmax values with 100, 200, and 400 mg of SPH3127 were 514.67, 1419.17, and 2513.33 ng/mL, respectively. The corresponding AUC0-24 values were 1638.14, 3096.20, and 7577.70 h × ng/mL. The median Tmax range from 0.33 to 1.0 h and the median t1/2 from 3 to 4 h. In an SAD, when the dose was >100 mg, plasma renin activity inhibition of up to 90% lasted up to 24 h. In MADs, renin activity was continuously inhibited by up to 90% in each group for 24 h after the last administration. Treatment-emergent adverse events (AEs) were reported in 29.2% of individuals receiving the SAD and 33.3% of those receiving MADs. Only mild adverse events occurred. IMPLICATIONS: SPH3127 was well tolerated and had robust and sustained suppression of plasma renin activity. CLINICALTRIALS. GOV IDENTIFIERS: NCT03128138 (SAD study) and NCT03255993 (MAD study).
Assuntos
Morfolinas , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Morfolinas/efeitos adversos , Morfolinas/farmacocinéticaRESUMO
CDK4/6 has been identified as an attractive therapeutic target for treatment of cancer. For unmet clinical needs, a novel class of imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives, which had distinctive triheteroaryl structure, had been discovered as CDK4/6 inhibitors. The compounds 10b and 10c, displayed the low nanomolar range activities on CDK4/6, desirable antiproliferative activities, excellent metabolic properties, and acceptable pharmacokinetic characters. In Colo-205 and U87MG xenograft models, compounds 10b and 10c also showed significant tumor growth inhibitions with controllable toxicities. All data confirmed that imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives 10b and 10c could be promising drug candidates for cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
The cyclin-dependent kinase (CDK)4/6-cyclin D1-Rb-p16/ink4a pathway is responsible for regulating cell progression past the G1 restriction point during the cell cycle. The development of a majority of human tumors is associated with dysregulation of this pathway, resulting in increased cancer cell proliferation. Both CDK4 and CDK6, well-validated cancer drug targets, function primarily as catalytic enzymes that mediate the phosphorylation of retinoblastoma protein (Rb). Here, we determined that SPH3643 is a novel potent antiproliferative agent that inhibits CDK4/6 kinase activity. In biochemical assays, SPH3643 showed more potent inhibition of both CDK4 and CDK6 than did 2 published CDK4/6 inhibitors, LY2835219 and palbociclib, and had better selectivity than LY2835219. Further in vitro study revealed that SPH3643 blocked Cdk/Rb signaling by inhibiting the phosphorylation of RbSer780 and arrested the MCF-7 cancer cells at G0 /G1 phase, resulting in marked inhibition of the proliferation of Rb-positive cancer cell lines. In vivo SPH3643 treatment in mice bearing xenograft tumor models of breast cancer, colon cancer, acute myelocytic leukemia, and glioblastoma resulted in significant decreases in tumor growth. SPH3643 was able to particularly strongly inhibit glioblastoma (U87-MG) cell growth in the brains of orthotopic carcinoma xenograft mice due to its high degree of intracerebral penetration and significant persistence in this setting. Together these results revealed that SPH3643 is a potent, orally active small-molecule inhibitor of CDK4/6 with robust anticancer efficacy and a high degree of blood-brain barrier permeability.
Assuntos
Antineoplásicos/farmacologia , Barreira Hematoencefálica/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: SPH3127 is a novel direct renin inhibitor designed as an oral drug for the regulation of blood pressure and body fluid homeostasis via the renin-angiotensin-aldosterone system (RAAS). This candidate is now being evaluated in a phase I clinical trial in China. OBJECTIVES: The purpose of this study is to investigate detailed nonclinical pharmacokinetic data, and to predict human pharmacokinetic parameters. METHODS: In vivo pharmacokinetic studies of SPH3127 were performed to investigate the exposure, absorption, clearance, distribution and metabolism after intravenous and oral administration in rats, beagle dogs and cynomolgus monkeys. The cynomolgus monkey pharmacokinetics/pharmacodynamics study was conducted to investigate the effect-concentration relationship of SPH3127. Its human pharmacokinetic properties were predicted employing an allometric scaling approach based on non-clinical species data. In vitro studies were also employed in a cytochrome P450 (CYP) enzyme phenotyping study, an inhibition and induction study, and a Caco-2 cell permeation and metabolites profile analysis. RESULTS: After a single intravenous administration of SPH3127 in rats and monkeys, high clearance and volume of distribution and a short terminal elimination half-life were seen for both species. The oral bioavailability of SPH3127 to rats and monkeys was about 11.5-24.5% and 3.3-11.3%, respectively, with the short peak time, Tmax, ranging from 0.25 to 1.3 h. SPH3127 shows low permeability across Caco-2 cell membranes, and as the substrate of p-gp with apparent efflux characteristics. SPH3127 is mainly distributed in the gastrointestine, liver, kidney, pancreas and lung after oral dose in rats, and which decreased quickly to a 1% peak concentration during 12 h. The plasma protein binding ratio of SPH3127 is low as 11.7-14.8% for all species. Excretion studies in rats suggested that fecal, urine and bile excretion represented about 15% of the intake dose, indicating that SPH3127 undergoes extensive metabolism after oral dosing. Phenotyping data revealed that CYP3A4 was the most active enzyme catalyzing the metabolism of SPH3127. The key metabolites were likely N-hydroxylation (M8-7), mono-oxidation-dehydrogenation (M7-4) and mono-oxidation (M8-1, M8-2), both for in vitro liver microsome incubation of all species and in vivo results in rats. The in vitro CYP inhibition study only found very weak action for CYP3A4 (midazolam 1'-hydroxylation) and CYP3A4 (midazolam 6ß-hydroxylation) with IC50 of 56.8 µM and 41.1 µM, respectively. Monkey pharmacokinetic/pharmacodynamic data showed favorable safety margins when compared with the exposure of the effect dose and that of the monkey NOAEL level. Simple four-species allometric scaling led to predicted human plasma clearance and volume of distribution, and then simulated the oral human plasma concentration-time profile, which are both in good consistency with phase I clinical trial pharmacokinetic data. CONCLUSIONS: SPH 3127 has appropriate pharmacokinetic properties for further clinical exploration.
Assuntos
Morfolinas/farmacocinética , Renina/antagonistas & inibidores , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Absorção Intestinal , Macaca fascicularis , Masculino , Taxa de Depuração Metabólica , Microssomos Hepáticos/metabolismo , Morfolinas/sangue , Morfolinas/química , Morfolinas/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
SPH3127, a newly developed oral nonpeptide direct renin inhibitor with good tolerance and favorable ADME (absorption distribution metabolism excretion) properties in preclinical species, is now being evaluated in phase Ι clinical trial. In this work, the subchronic toxicity of SPH3127 in Sprague-Dawley rats and cynomolgus monkeys has been characterized. Rats and monkeys received SPH3127 orally (30, 300, 900 and 20, 100, 450â¯mg/kg/day, respectively) on a consecutive daily dosing schedule for 28 days followed by a 28-days recovery period for one third of the animals. The adverse effects of SPH3127 on rats and monkeys mainly included kidney and cardiovascular toxicity, which were consistent with pharmacologic perturbations of physiologic processes associated with the intended molecular targets for this class of renin signaling inhibitors. Moderate liver weight increases accompanied by CYP3A induction were seen in 300 and 900â¯mg/kg/day rats but not in monkeys or in vitro human hepatocytes. One 450â¯mg/kg/day monkey died early at day 23 with apparent myelosuppression characterized by atrophy of thymus and spleen, and the relevance to the action of SPH3127 remained unclear. Most of the treatment-induced effects were reversible upon discontinuation of treatment. The no-observed-adverse-effect level (NOAEL) of SPH3127 was determined to be 30â¯mg/kg/day for Sprague-Dawley rats and 20â¯mg/kg/day for cynomolgus monkeys based on the kidney and cardiovascular changes found at mid- and high-dose animals.
Assuntos
Cardiotoxicidade/etiologia , Inibidores Enzimáticos/toxicidade , Rim/efeitos dos fármacos , Morfolinas/toxicidade , Renina/antagonistas & inibidores , Administração Oral , Animais , Células Cultivadas , Citocromo P-450 CYP3A/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Feminino , Hepatócitos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Macaca fascicularis , Masculino , Modelos Animais , Morfolinas/administração & dosagem , Nível de Efeito Adverso não Observado , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Timo/efeitos dos fármacosRESUMO
Targeting CDK4/6 has been identified as an effective therapeutics for treatment of cancer. We herein reported the discovery of a series of 6-(2-(methylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine derivatives as CDK4/6 inhibitors against cancer. Compound 3c, which displayed high potency and selectivity on CDK4/6 (IC50â¯=â¯0.710/1.10â¯nM) over a variety of other kinases, possessed desirable antiproliferative activities, excellent metabolic properties, and favorable pharmacokinetic characters. In MCF-7, Colo-205, and A549 xenograft models, compound 3c exhibited significant tumor growth inhibitions with low toxicities, which could be a promising drug candidate for further development.
Assuntos
Antineoplásicos/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
c-Met/HGF signaling pathway plays an important role in cancer progression, and it was considered to be related to poor prognosis and drug resistance. Based on metabolite profiling of (S)-7-fluoro-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyrazin-1-yl)ethyl)quinoline (1), a series of 2-substituted or 3-substituted-6-(1-(1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)quinoline derivatives was rationally designed and evaluated. Most of the 3-substituted derivatives not only exhibited potent activities in both enzymatic and cellular assays, but also were stable in liver microsomes among different species (human, rat and monkey). SAR investigation revealed that introducing of N-methyl-1H-pyrazol-4-yl group at the 3-position of quinoline moiety is beneficial to improve the inhibitory potency, especially in the cellular assays. The influence of fluorine atom at 7-position or 5, 7-position of quinoline moiety and substituents at the 6-position of triazolo[4,5-b]pyrazine core on overall activity is not very significant. Racemate 14, an extremely potent and exquisitely selective c-Met inhibitor, demonstrated favorable pharmacokinetic properties in rats, no significant AO metabolism, and effective tumor growth inhibition in c-Met overexpressed NSCLC (H1993 cell line) and gastric cancer (SNU-5 cell line) xenograft models. Docking analysis indicated that besides the typical interactions of most selective c-Met inhibitors, the intramolecular halogen bond and additional hydrogen bond interactions with kinase are beneficial to the binding. These results may provide deep insight into potential structural modifications for developing potent c-Met inhibitors.
Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Quinolinas/química , Quinolinas/uso terapêutico , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Feminino , Mucosa Gástrica/metabolismo , Haplorrinos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirazinas/química , Pirazinas/farmacocinética , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Quinolinas/farmacocinética , Quinolinas/farmacologia , Ratos , Ratos Sprague-Dawley , Estômago/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismoRESUMO
Aberrant c-Met activation has been implicated in multiple tumor oncogenic processes and drug resistance. In this study, a series of imidazo[4,5-b]pyrazine derivatives was designed and synthesized, and their inhibitory activities were evaluated in vitro. Structure-activity relationship (SAR) was investigated systematically and docking analysis was performed to elucidate the binding mode, leading to the identification of the most promising compound 1D-2 which exhibited significant inhibitory effect on both enzymatic (IC50=1.45nM) and cellular (IC50=24.7nM in H1993 cell line) assays, as well as exquisite selectivity and satisfactory metabolic stability in human and rat liver microsomes.
Assuntos
Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirazinas/farmacologia , Animais , Células CACO-2 , Humanos , Imidazóis/síntese química , Imidazóis/química , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazinas/síntese química , Pirazinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
The signal transduction of acetylated histone can be processed through a recognition module, bromodomain. Several inhibitors targeting BRD4, one of the bromodomain members, are in clinical trials as anticancer drugs. Hereby, we report our efforts on discovery and optimization of a new series of 2-thiazolidinones as BRD4 inhibitors along our previous study. In this work, guided by crystal structure analysis, we reversed the sulfonamide group and identified a new binding mode. A structure-activity relationship study on this new series led to several potent BRD4 inhibitors with IC50 of about 0.05-0.1 µM in FP binding assay and GI50 of 0.1-0.3 µM in cell based assays. To complete the lead-like assessment of this series, we further checked its effects on BRD4 downstream protein c-Myc, investigated its selectivity among five different bromodomain proteins, as well as the metabolic stability test, and reinforced the utility of 2-thiazolidinone scaffold as BET bromodomain inhibitors in novel anticancer drug development.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Descoberta de Drogas , Proteínas Nucleares/antagonistas & inibidores , Tiazolidinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Antineoplásicos/síntese química , Proteínas de Ciclo Celular , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Tiazolidinas/síntese química , Tiazolidinas/química , Células Tumorais CultivadasRESUMO
Gatekeeper T790 M mutation in EGFR is the most prevalent factor underlying acquired resistance. Acrylamide-bearing quinazoline derivatives are powerful irreversible inhibitors for overcoming resistance. Nevertheless, concerns about the risk of nonspecific covalent modification have motivated the development of novel cysteine-targeting inhibitors. In this paper, we demonstrate that fluoro-substituted olefins can be tuned to alter Michael addition reactivity. Incorporation of these olefins into the quinazoline templates produced potent EGFR inhibitors with improved safety and pharmacokinetic properties. A lead compound 5a was validated against EGFR(WT), EGFR(T790M) as well as A431 and H1975 cancer cell lines. Additionally, compound 5a displayed a weaker inhibition against the EGFR-independent cancer cell line SW620 when compared with afatinib. Oral administration of 5a at a dose of 30 mg/kg induced tumor regression in a murine-EGFR(L858R/T790M) driven H1975 xenograft model. Also, 5a exhibited improved oral bioavailability and safety as well as favorable tissue distribution properties and enhanced brain uptake. These findings provide the basis of a promising strategy toward the treatment of NSCLC patients with drug resistance.
Assuntos
Antineoplásicos/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos Endogâmicos BALB C , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
R adamantly beats S: 11ß-HSD1 is a target for treating metabolic syndrome. The R isomer 5 was selected as a starting point for optimization and SAR studies. Inhibitor 8 w emerged after several rounds of optimization, showing cross-species inhibition of human and mouse 11ß-HSD1. It also displays a good DMPK profile in vitro, and was advanced to PK/PD evaluations in vivo. The results confirmed its dose-dependent activity in mice.