RESUMEN
The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.
Asunto(s)
Antineoplásicos , Mutación , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Humanos , Animales , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Estructura-Actividad , Ratones , Línea Celular Tumoral , Sulfonamidas/farmacología , Sulfonamidas/química , Ratas , Descubrimiento de DrogasRESUMEN
Bruton's tyrosine kinase (BTK) plays an essential role in B-cell receptor (BCR)-mediated signaling as well as the downstream signaling pathway for Fc receptors (FcRs). Targeting BTK for B-cell malignancies by interfering with BCR signaling has been clinically validated by some covalent inhibitors, but suboptimal kinase selectivity may lead to some adverse effects, which also makes the clinical development of autoimmune disease therapy more challenging. The structure-activity relationship (SAR) starting from zanubrutinib (BGB-3111) leads to a series of highly selective BTK inhibitors, in which BGB-8035 is located in the ATP binding pocket and has similar hinge binding to ATP but exhibits high selectivity over other kinases (EGFR, Tec, etc.). With an excellent pharmacokinetic profile as well as demonstrated efficacy studies in oncology and autoimmune disease models, BGB-8035 has been declared a preclinical candidate. However, BGB-8035 showed an inferior toxicity profile compared to that of BGB-3111.
Asunto(s)
Enfermedades Autoinmunes , Neoplasias , Humanos , Agammaglobulinemia Tirosina Quinasa , Relación Estructura-Actividad , Enfermedades Autoinmunes/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Adenosina Trifosfato , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinéticaRESUMEN
Radioactive iodine in nuclear waste is increasingly harmful to the human body and the environment because of its strong radioactivity, high fluidity, easy solubility in water, and long half-life. It is very important to find clean and economical materials to recover and fix radioactive iodine. In this paper, the amino-metal-organic framework was covalently modified to obtain composite materials to improve the recycling of iodine in the environment. These adsorbents are used to adsorb iodine in water, showing outstanding adsorption performance. The adsorption data are in good agreement with the Langmuir isothermal adsorption model and pseudo-second-order kinetic model, indicating that the adsorption process is mainly monolayer adsorption and chemical adsorption. The two materials showed selective adsorption capacity for iodine in the solution containing multiple competing ions. The adsorption capacity of the covalently modified composite increased from 949.52 to 2157.44 mg/g. Compared with the amino-metal-organic framework, the modified composite contains more electron-rich groups as active sites, and forms charge transfer compounds with iodine to realize chemical adsorption. Through the simulated adsorption of ultra-high-pressure micro-jet, the material has certain working ability under high pressure, which provides a theoretical basis for the future recovery and utilization of iodine under high pressure.
Asunto(s)
Yodo , Estructuras Metalorgánicas , Neoplasias de la Tiroides , Contaminantes Químicos del Agua , Humanos , Adsorción , Estructuras Metalorgánicas/química , Radioisótopos de Yodo , Contaminantes Químicos del Agua/análisis , Yoduros , AguaRESUMEN
In this study, a promising process has been developed for selective recovery of valuable metals from spent lithium ion batteries (LIBs). First, reduction roasting which used spent anode powder as reduction agent and water immersion are applied to preferentially recover lithium. Subsequently, an ammonia leaching method is adopted to eï¬ ;ectively separate nickel and cobalt from water immersion residue. Results indicate that Li2CO3, (NiO)m·(MnO)n, Ni, Co are the ultimate reduction products at 650 °C for 1â¯h with 5% anode powder. 82.2 % Li is preferentially leached via water immersion after reduction roasting and Li2CO3 products are obtained by evaporation crystallization. Thermodynamics shows that reducing ammonia leaching is feasible for water immersion residue. Amounts of 97.7 % Ni and 99.1 % Co can be selectively leached by NH3·H2O and (NH4)2SO3 while Mn remain in the residue as (NH4)2Mn(SO3)2·H2O, (NH4)2Mn(SO4)2·6H2O and (NH4)2Mn2(SO3)3 under the optimized conditions. Ammonia leaching kinetic show the activation energy of Ni and Co is 84.44â¯kJ/mol and 91.73â¯kJ/mol, which indicate the controlling steps are the chemical reaction. Summarily, the whole process achieves the maximum degree of selective recovery and reduces the environmental pollution caused by the multistep purification.
RESUMEN
Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, 139), which displays excellent PARP-1 and PARP-2 inhibition with IC50 of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC50 = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17-19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.
Asunto(s)
Fluorenos/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Poli(ADP-Ribosa) Polimerasas/química , Animales , Sitios de Unión , Carbazoles/química , Carbazoles/metabolismo , Carbazoles/farmacología , Carbazoles/uso terapéutico , Proliferación Celular/efectos de los fármacos , Perros , Femenino , Fluorenos/metabolismo , Fluorenos/farmacología , Fluorenos/uso terapéutico , Semivida , Humanos , Indoles/química , Indoles/metabolismo , Indoles/farmacología , Indoles/uso terapéutico , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Ratones , Microsomas/metabolismo , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Pamiparib, an investigational Poly (ADP-ribose) polymerase (PARP) inhibitor in clinical development, demonstrates excellent selectivity for both PARP1 and PARP2, and superb anti-proliferation activities in tumor cell lines with BRCA1/2 mutations or HR pathway deficiency (HRD). Pamiparib has good bioavailability and is 16-fold more potent than olaparib in an efficacy study using BRCA1 mutated MDA-MB-436 breast cancer xenograft model. Pamiparib also shows strong anti-tumor synergy with temozolomide (TMZ), a DNA alkylating agent used to treat brain tumors. Compared to other PARP inhibitors, pamiparib demonstrated improved penetration across the blood brain barrier (BBB) in mice. Oral administration of pamiparib at a dose as low as 3â¯mg/kg is sufficient to abrogate PARylation in brain tumor tissues. In SCLC-derived, TMZ-resistant H209 intracranial xenograft model, combination of pamiparib with TMZ overcomes its resistance and shows significant tumor inhibitory effects and prolonged life span. Our data suggests that combination of pamiparib with TMZ has unique potential for treatment of brain tumors. Currently, the combination therapy of pamiparib with TMZ is evaluated in clinical trial [NCT03150862].
Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Fluorenos/farmacología , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Animales , Apoptosis , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Wild-type isocitrate dehydrogenase-expressing glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median age at diagnosis of ≥65 years. It accounts for approximately 90% of all GBMs and has a median overall survival (OS) of <15 months. Although immune checkpoint blockade (ICB) therapy has achieved remarkable survival benefits in a variety of aggressive malignancies, similar success has yet to be achieved for GBM among phase III clinical trials to date. Our study aimed to understand the relationship between subject age and immunotherapeutic efficacy as it relates to survival from glioma. EXPERIMENTAL DESIGN: (i) Clinical data: GBM patient datasets from The Cancer Genome Atlas, Northwestern Medicine Enterprise Data Warehouse, and clinical studies evaluating ICB were stratified by age and compared for OS. (ii) Animal models: young, middle-aged, and older adult wild-type and indoleamine 2,3 dioxygenase (IDO)-knockout syngeneic mice were intracranially engrafted with CT-2A or GL261 glioma cell lines and treated with or without CTLA-4/PD-L1 mAbs, or radiation, anti-PD-1 mAb, and/or a pharmacologic IDO enzyme inhibitor. RESULTS: Advanced age was associated with decreased GBM patient survival regardless of treatment with ICB. The advanced age-associated increase of brain IDO expression was linked to the suppression of immunotherapeutic efficacy and was not reversed by IDO enzyme inhibitor treatment. CONCLUSIONS: Immunosuppression increases in the brain during advanced age and inhibits antiglioma immunity in older adults. Going forward, it will be important to fully understand the factors and mechanisms in the elderly brain that contribute to the decreased survival of older patients with GBM during treatment with ICB.
Asunto(s)
Encéfalo/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Isocitrato Deshidrogenasa/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Animales , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Encéfalo/inmunología , Encéfalo/patología , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/genética , Senescencia Celular/efectos de los fármacos , Senescencia Celular/inmunología , Modelos Animales de Enfermedad , Femenino , Glioblastoma/genética , Glioblastoma/inmunología , Glioblastoma/patología , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Terapia de Inmunosupresión/efectos adversos , Terapia de Inmunosupresión/métodos , Masculino , Ratones Noqueados , Persona de Mediana Edad , Supervivencia sin ProgresiónRESUMEN
The mutation of K-RAS represents one of the most frequent genetic alterations in cancer. Targeting of downstream effectors of RAS, including of MEK and ERK, has limited clinical success in cancer patients with K-RAS mutations. The reduced sensitivity of K-RAS-mutated cells to certain MEK inhibitors (MEKi) is associated with the feedback phosphorylation of MEK by C-RAF and with the reactivation of mitogen-activated protein kinase (MAPK) signaling. Here, we report that the RAF dimer inhibitors lifirafenib (BGB-283) and compound C show a strong synergistic effect with MEKi, including mirdametinib (PD-0325901) and selumetinib, in suppressing the proliferation of K-RAS-mutated non-small-cell lung cancer and colorectal cancer (CRC) cell lines. This synergistic effect was not observed with the B-RAFV600E selective inhibitor vemurafenib. Our mechanistic analysis revealed that RAF dimer inhibition suppresses RAF-dependent MEK reactivation and leads to the sustained inhibition of MAPK signaling in K-RAS-mutated cells. This synergistic effect was also observed in several K-RAS mutant mouse xenograft models. A pharmacodynamic analysis supported a role for the synergistic phospho-ERK blockade in enhancing the antitumor activity observed in the K-RAS mutant models. These findings support a vertical inhibition strategy in which RAF dimer and MEKi are combined to target K-RAS-mutated cancers, and have led to a Phase 1b/2 combination therapy study of lifirafenib and mirdametinib in solid tumor patients with K-RAS mutations and other MAPK pathway aberrations.
Asunto(s)
Antineoplásicos/farmacología , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Mutación/genética , Inhibidores de Proteínas Quinasas/farmacología , Multimerización de Proteína , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Regulación Alostérica/efectos de los fármacos , Animales , Bencimidazoles/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Multimerización de Proteína/efectos de los fármacos , Factores de Tiempo , Regulación hacia Arriba/efectos de los fármacos , Vemurafenib/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Aberrant activation of Bruton's tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematological malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclinical characterization of a potent, selective, and irreversible BTK inhibitor as our clinical candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compounds. Compound BGB-3111 (31a, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Antineoplásicos/farmacología , Descubrimiento de Drogas , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Agammaglobulinemia Tirosina Quinasa/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Piperidinas/síntesis química , Piperidinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Acute limb ischemia is one of the most common peripheral arterial disease, while surgical restoration of blood flow often results in ischemia/reperfusion (I/R) injury. Our previous study revealed the inflammation intensity in arterial tissue, characterized by expression of high mobility group box protein 1 (HMGB1), was contrary to the fluctuation of hemodynamics in reperfusion limbs in a rat model. This study meant to clarify the role of HMGB1 during this process. Laser Doppler perfusion imaging evaluated limb hemodynamics in mean and max perfusion unit (PU). Femoral arterial tissue was collected for molecular biology examination. The results revealed that HMGB1 promoted vascular structure remodeling and vasomotor dysfunction during acute I/R, characterized by degradation of collagenous fibers, disruption of elastic lamellae, intensive inflammation and phenotype transfer of smooth muscle cells. Blockade of HMGB1 preserved vascular homeostasis and improved PUs (PmeanPU<0.001, PmaxPU<0.001). The elevated expression of TNF-α, IL-6, ICAM, VCAM, MMP-2, MMP-9, α-SM actin correlated with HMGB1 positively. In conclusion, HMGB1 promoted vascular remodeling and dysfunction via initiating an inflammation cascade during I/R. Blockade of HMGB1 would preserve vascular homeostasis and facilitate the blood perfusion of ischemic limb.
Asunto(s)
Antiinflamatorios/farmacología , Proteína HMGB1/antagonistas & inhibidores , Hemorreología/efectos de los fármacos , Heparina/farmacología , Músculo Esquelético/irrigación sanguínea , Piruvatos/farmacología , Daño por Reperfusión/prevención & control , Actinas/metabolismo , Animales , Velocidad del Flujo Sanguíneo , Modelos Animales de Enfermedad , Proteína HMGB1/metabolismo , Miembro Posterior , Mediadores de Inflamación/metabolismo , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratas Wistar , Recuperación de la Función , Flujo Sanguíneo Regional , Daño por Reperfusión/metabolismo , Daño por Reperfusión/fisiopatología , Transducción de Señal/efectos de los fármacos , Remodelación Vascular/efectos de los fármacosRESUMEN
In a search for novel small molecule calcium-sensing receptor (CaSR) antagonists as oral bone anabolic agents, we discovered dihydrobenzofuran cyclopropane carboxylic acid derivatives, such as 12f (IC50=27.6nM), are highly potent calcium-sensing receptor antagonists. Studies in rats established that compound 12f stimulates parathyroid hormone (PTH) release in a fast-acting, pulsatile manner.
Asunto(s)
Benzofuranos/química , Ciclopropanos/metabolismo , Osteoporosis/tratamiento farmacológico , Receptores Sensibles al Calcio/antagonistas & inhibidores , Administración Oral , Animales , Benzofuranos/metabolismo , Benzofuranos/farmacocinética , Benzofuranos/uso terapéutico , Ciclopropanos/química , Ciclopropanos/farmacocinética , Ciclopropanos/uso terapéutico , Evaluación Preclínica de Medicamentos , Femenino , Semivida , Osteoporosis/patología , Hormona Paratiroidea/sangre , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores Sensibles al Calcio/metabolismo , Relación Estructura-ActividadRESUMEN
Oncogenic BRAF, which drives cell transformation and proliferation, has been detected in approximately 50% of human malignant melanomas and 5% to 15% of colorectal cancers. Despite the remarkable clinical activities achieved by vemurafenib and dabrafenib in treating BRAF(V600E) metastatic melanoma, their clinical efficacy in BRAF(V600E) colorectal cancer is far less impressive. Prior studies suggested that feedback activation of EGFR and MAPK signaling upon BRAF inhibition might contribute to the relative unresponsiveness of colorectal cancer to the first-generation BRAF inhibitors. Here, we report characterization of a dual RAF kinase/EGFR inhibitor, BGB-283, which is currently under clinical investigation. In vitro, BGB-283 potently inhibits BRAF(V600E)-activated ERK phosphorylation and cell proliferation. It demonstrates selective cytotoxicity and preferentially inhibits proliferation of cancer cells harboring BRAF(V600E) and EGFR mutation/amplification. In BRAF(V600E) colorectal cancer cell lines, BGB-283 effectively inhibits the reactivation of EGFR and EGFR-mediated cell proliferation. In vivo, BGB-283 treatment leads to dose-dependent tumor growth inhibition accompanied by partial and complete tumor regressions in both cell line-derived and primary human colorectal tumor xenografts bearing BRAF(V600E) mutation. These findings support BGB-283 as a potent antitumor drug candidate with clinical potential for treating colorectal cancer harboring BRAF(V600E) mutation.
Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Naftiridinas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Quinasas raf/antagonistas & inhibidores , Animales , Dominio Catalítico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Receptores ErbB/genética , Receptores ErbB/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Sistema de Señalización de MAP Quinasas , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Modelos Moleculares , Fosforilación , Unión Proteica , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Carga Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas raf/metabolismoAsunto(s)
Arteria Femoral/metabolismo , Proteína HMGB1/antagonistas & inhibidores , Proteína HMGB1/biosíntesis , Heparina/farmacología , Daño por Reperfusión/metabolismo , Animales , Regulación de la Expresión Génica , Heparina/uso terapéutico , Miembro Posterior/irrigación sanguínea , Miembro Posterior/efectos de los fármacos , Miembro Posterior/metabolismo , Masculino , Distribución Aleatoria , Ratas , Ratas Wistar , Daño por Reperfusión/tratamiento farmacológicoRESUMEN
The design, synthesis, and structure-activity relationship (SAR) for a series of ß-substituted 3-(4-aryloxyaryl)propanoic acid GPR40 agonists is described. Systematic replacement of the pendant aryloxy group led to identification of potent GPR40 agonists. In order to identify candidates suitable for in vivo validation of the target, serum shifted potency and pharmacokinetic properties were determined for several compounds. Finally, further profiling of compound 7 is presented, including demonstration of enhanced glucose tolerance in an in vivo mouse model.
Asunto(s)
Hipoglucemiantes/farmacología , Islotes Pancreáticos/efectos de los fármacos , Propionatos/síntesis química , Propionatos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Ciclización , Modelos Animales de Enfermedad , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Propionatos/química , Propionatos/farmacocinéticaRESUMEN
A series of benzimidazole pyrrolidinyl amides containing a piperidinyl group were discovered as novel prolylcarboxypeptidase (PrCP) inhibitors. Low-nanomolar IC(50)'s were achieved for several analogs, of which compound 9b displayed modest ex vivo target engagement in eDIO mouse plasma. Compound 9b was also studied in vivo for its effect on weight loss and food intake in an eDIO mouse model and the results will be discussed.
Asunto(s)
Amidas , Bencimidazoles , Carboxipeptidasas/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos , Pirrolidinas , Amidas/química , Amidas/farmacología , Animales , Bencimidazoles/química , Bencimidazoles/farmacología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Pirrolidinas/química , Pirrolidinas/farmacología , Relación Estructura-ActividadRESUMEN
Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC(50) values of 1 and 2 nM and is not active (IC(50) > 25 µM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP(-/-) and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Bencimidazoles/síntesis química , Carboxipeptidasas/antagonistas & inhibidores , Fenilalanina/análogos & derivados , Inhibidores de Serina Proteinasa/síntesis química , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/farmacología , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Carboxipeptidasas/genética , Diseño de Fármacos , Humanos , Masculino , Ratones , Ratones Noqueados , Obesidad/tratamiento farmacológico , Obesidad/enzimología , Fenilalanina/síntesis química , Fenilalanina/farmacocinética , Fenilalanina/farmacología , Unión Proteica , Inhibidores de Serina Proteinasa/farmacocinética , Inhibidores de Serina Proteinasa/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Systematic structure-activity relationship (SAR) studies of a screening lead led to the discovery of a series of thiazolidinediones (TZDs) as potent GPR40 agonists. Among them, compound C demonstrated an acute mechanism-based glucose-lowering in an intraperitoneal glucose tolerance test (IPGTT) in lean mice, while no effects were observed in GPR40 knock-out mice.
Asunto(s)
Descubrimiento de Drogas/métodos , Receptores Acoplados a Proteínas G/agonistas , Tiazolidinedionas/química , Animales , Ratones , Ratones Noqueados , Unión Proteica/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-Actividad , Tiazolidinedionas/agonistas , Tiazolidinedionas/farmacologíaRESUMEN
A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.
Asunto(s)
Química Farmacéutica/métodos , Receptores CCR2/antagonistas & inhibidores , Receptores CCR2/química , Administración Oral , Animales , Quimiotaxis , Perros , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Macaca mulatta , Modelos Químicos , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
OBJECTIVE: Acute activation of G protein-coupled receptor 40 (GPR40) by free fatty acids (FFAs) or synthetic GPR40 agonists enhances insulin secretion. However, it is still a matter of debate whether activation of GPR40 would be beneficial for the treatment of type 2 diabetes, since chronic exposure to FFAs impairs islet function. We sought to evaluate the specific role of GPR40 in islets and its potential as a therapeutic target using compounds that specifically activate GPR40. RESEARCH DESIGN AND METHODS: We developed a series of GPR40-selective small-molecule agonists and studied their acute and chronic effects on glucose-dependent insulin secretion (GDIS) in isolated islets, as well as effects on blood glucose levels during intraperitoneal glucose tolerance tests in wild-type and GPR40 knockout mice (GPR40(-/-)). RESULTS: Small-molecule GPR40 agonists significantly enhanced GDIS in isolated islets and improved glucose tolerance in wild-type mice but not in GPR40(-/-) mice. While a 72-h exposure to FFAs in tissue culture significantly impaired GDIS in islets from both wild-type and GPR40(-/-) mice, similar exposure to the GPR40 agonist did not impair GDIS in islets from wild-type mice. Furthermore, the GPR40 agonist enhanced insulin secretion in perfused pancreata from neonatal streptozotocin-induced diabetic rats and improved glucose levels in mice with high-fat diet-induced obesity acutely and chronically. CONCLUSIONS: GPR40 does not mediate the chronic toxic effects of FFAs on islet function. Pharmacological activation of GPR40 may potentiate GDIS in humans and be beneficial for overall glucose control in patients with type 2 diabetes.
Asunto(s)
Glucemia/metabolismo , Insulina/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Receptores Acoplados a Proteínas G/agonistas , Animales , Animales Recién Nacidos , Células CHO , Línea Celular , Cricetinae , Cricetulus , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Grasas de la Dieta/administración & dosificación , Ácidos Grasos/farmacología , Ácidos Grasos no Esterificados/farmacología , Femenino , Humanos , Técnicas In Vitro , Inositol 1,4,5-Trifosfato/metabolismo , Insulina/sangre , Secreción de Insulina , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/sangre , Obesidad/etiología , Obesidad/metabolismo , Embarazo , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiologíaRESUMEN
Introduction of ring restrictions to a linear aminobutyramide CC chemokine receptor 2 (CCR2) antagonist lead (2) led to the discovery of a 1,3-disubstituted cyclopentane scaffold with enhanced hCCR2 receptor binding and antagonist activity. (1S,3R)-N-[3,5-Bis(trifluoromethyl)benzyl]-1-methyl-3-[(1R,3'R)-methyl-1'H-spiro[indene-1,4'-piperidin]-1'-yl]cyclopentanecarboxamide (16) had IC50 of 1.3 nM (binding) and 0.45 nM (functional chemotaxis) against hCCR2. It also showed activity against the mouse CCR2 receptor with an IC50 of 130 nM. Compound 16 is selective against other chemokine receptors, including CCR5 ( approximately 500-fold).