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1.
J Clin Oncol ; 42(24): 2928-2938, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-38900987

RESUMEN

PURPOSE: Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma. METHODS: Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti-PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria. RESULTS: ORRs were 63% for patients with anti-PD-1-naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment-naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti-PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti-PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded. CONCLUSION: The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti-PD-1 therapy in the adjuvant, but not advanced, setting.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Proteína del Gen 3 de Activación de Linfocitos , Melanoma , Humanos , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Melanoma/patología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Anciano de 80 o más Años , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Supervivencia sin Progresión
2.
Cancer Res ; 83(2): 301-315, 2023 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-36351060

RESUMEN

Effective treatments for de novo and treatment-emergent small-cell/neuroendocrine (t-SCNC) prostate cancer represent an unmet need for this disease. Using metastatic biopsies from patients with advanced cancer, we demonstrate that delta-like ligand 3 (DLL3) is expressed in de novo and t-SCNC and is associated with reduced survival. We develop a PET agent, [89Zr]-DFO-DLL3-scFv, that detects DLL3 levels in mouse SCNC models. In multiple patient-derived xenograft models, AMG 757 (tarlatamab), a half-life-extended bispecific T-cell engager (BiTE) immunotherapy that redirects CD3-positive T cells to kill DLL3-expressing cells, exhibited potent and durable antitumor activity. Late relapsing tumors after AMG 757 treatment exhibited lower DLL3 levels, suggesting antigen loss as a resistance mechanism, particularly in tumors with heterogeneous DLL3 expression. These findings have been translated into an ongoing clinical trial of AMG 757 in de novo and t-SCNC, with a confirmed objective partial response in a patient with histologically confirmed SCNC. Overall, these results identify DLL3 as a therapeutic target in SCNC and demonstrate that DLL3-targeted BiTE immunotherapy has significant antitumor activity in this aggressive prostate cancer subtype. SIGNIFICANCE: The preclinical and clinical evaluation of DLL3-directed immunotherapy, AMG 757, and development of a PET radiotracer for noninvasive DLL3 detection demonstrate the potential of targeting DLL3 in SCNC prostate cancer.


Asunto(s)
Proteínas de la Membrana , Neoplasias de la Próstata , Animales , Humanos , Masculino , Ratones , Anticuerpos Monoclonales , Inmunoterapia , Péptidos y Proteínas de Señalización Intracelular/inmunología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ligandos , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Tomografía de Emisión de Positrones , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/terapia , Neoplasias de la Próstata/patología , Circonio , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/terapia
3.
ACS Med Chem Lett ; 10(6): 911-916, 2019 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-31223447

RESUMEN

Lead optimization of the diphenylpyridylethanamine (DPPE) and triphenylethanamine (TPE) series of CETP inhibitors to improve their pharmaceutical profile is described. Polar groups at the N-terminus position in the DPPE series resulted in further improvement in potency and pharmaceutical properties concomitant with retaining the safety, efficacy, and pharmacokinetic (PK) profile. A structure-activity relationship observed in the DPPE series was extended to the corresponding analogs in the more potent TPE series, and further optimization resulted in the identification of 2-amino-N-((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanamide (13). Compound 13 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemetry rats, had an excellent PK profile, and demonstrated robust efficacy in human CETP/apo-B-100 dual transgenic mice and in hamsters.

4.
J Pharm Sci ; 107(5): 1352-1360, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29317226

RESUMEN

BMS-A is an inhibitor of cholesteryl ester transfer protein and is a highly lipophilic compound (clogP 10.5) with poor aqueous solubility (<0.0001 mg/mL at pH 6.5). The compound exhibits low oral exposure when dosed as cosolvent solution formulations. The purpose of this study was to evaluate lipid-based formulations for enabling high-dose toxicology studies and enhancing toxicology margins of BMS-A in preclinical studies in nonrodent species. The solubility of BMS-A was screened in lipid and cosolvent/surfactant excipients, and prototype formulations were developed. In vitro tests showed that fine/microemulsions were formed after aqueous dilution of lipid formulations, and BMS-A was transferred from oil phase to aqueous phase with enhanced solubility following lipid digestion. When dosed in dogs at 200 mg/kg, a Gelucire-based formulation exhibited more than 10-fold higher exposure compared to the solution formulation and was thus selected for toxicology studies in dogs. For monkeys, an olive oil formulation was developed, and the exposure was about 7-fold higher than that from the solution. In summary, lipid-based drug delivery could be applied in early stages of drug discovery to enhance oral exposure and enable preclinical toxicology studies of highly lipophilic compounds, while facilitating the candidate selection of a molecule which is more specifically designed for bioperformance in a lipid-based drug delivery strategy.


Asunto(s)
Benzamidas/administración & dosificación , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Emulsiones/química , Excipientes/química , Fluorobencenos/administración & dosificación , Lípidos/química , Administración Oral , Animales , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Disponibilidad Biológica , Perros , Composición de Medicamentos , Estabilidad de Medicamentos , Fluorobencenos/efectos adversos , Fluorobencenos/farmacocinética , Macaca fascicularis , Masculino , Ratones Endogámicos BALB C , Aceite de Oliva/química , Solubilidad , Triglicéridos/química , Agua/química
5.
Bioorg Med Chem Lett ; 26(14): 3278-3281, 2016 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-27256912

RESUMEN

Hydroxyl 1,2-diphenylethanamine analogs were identified as potent inhibitors of cholesterol ester transfer protein (CETP), a therapeutic target to raise HDL cholesterol. In an effort to improve the pharmaceutical properties in the previously disclosed DiPhenylPyridineEthanamine (DPPE) series, polar groups were introduced to the N-linked quaternary center. Optimization of analogues for potency, in vitro liability profile and efficacy led to identification of lead compound 16 which demonstrated robust pharmacodynamic effects in human CETP/apo-B100 dual transgenic mice.


Asunto(s)
Aminas/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Descubrimiento de Drogas , Aminas/síntesis química , Aminas/química , Animales , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Transgénicos , Estructura Molecular , Relación Estructura-Actividad
6.
J Med Chem ; 58(22): 9010-26, 2015 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-26524347

RESUMEN

Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.


Asunto(s)
Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Bencilaminas/síntesis química , Bencilaminas/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Animales , Anticolesterolemiantes/farmacocinética , Aterosclerosis/tratamiento farmacológico , Benzamidas/farmacocinética , Bencilaminas/farmacocinética , Presión Sanguínea/efectos de los fármacos , Línea Celular , Colesterol/metabolismo , HDL-Colesterol/sangre , Cricetinae , Citocromo P-450 CYP11B2/antagonistas & inhibidores , Perros , Descubrimiento de Drogas , Humanos , Macaca fascicularis , Masculino , Mesocricetus , Ratones , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Quinolinas/farmacología , Ratas , Ratas Sprague-Dawley
7.
ACS Med Chem Lett ; 6(8): 908-12, 2015 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-26288692

RESUMEN

BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.

8.
J Clin Oncol ; 33(18): 2004-12, 2015 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-25897158

RESUMEN

PURPOSE: Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non-small-cell lung cancer (NSCLC) receiving nivolumab in this trial. PATIENTS AND METHODS: Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. RESULTS: Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. CONCLUSION: Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Estudios de Cohortes , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Nivolumab , Receptor de Muerte Celular Programada 1/metabolismo , Resultado del Tratamiento
9.
Bioorg Med Chem Lett ; 25(21): 4983-4986, 2015 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-25801931

RESUMEN

Phenethyl aminoheterocycles like compound 1 were known to be potent I(Kur) blockers although they lacked potency in vivo. Modification of the heterocycle led to the design and synthesis of pseudosaccharin amines. Compounds such as 14, 17d and 21c were found to be potent K(V)1.5 blockers and selective over other cardiac ion channels. These compounds had potent pharmacodynamic activity, however, they also showed off-target activities such as hemodynamic effects.


Asunto(s)
Aminas/farmacología , Canal de Potasio Kv1.5/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/farmacología , Aminas/síntesis química , Aminas/química , Animales , Presión Sanguínea/efectos de los fármacos , Ciclohexanos/química , Ciclohexanos/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Canal de Potasio Kv1.5/metabolismo , Ratones , Estructura Molecular , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/química , Conejos , Ratas , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Relación Estructura-Actividad
12.
J Med Chem ; 55(13): 6162-75, 2012 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-22650305

RESUMEN

A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.


Asunto(s)
Anticolesterolemiantes/química , Anticolesterolemiantes/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Piridinas/química , Piridinas/farmacología , Estilbenos/química , Estilbenos/farmacología , Animales , Anticolesterolemiantes/síntesis química , Apolipoproteína B-100/antagonistas & inhibidores , Apolipoproteína B-100/metabolismo , Presión Sanguínea/efectos de los fármacos , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Enfermedad Coronaria/tratamiento farmacológico , Cricetinae , Descubrimiento de Drogas , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Ratones Transgénicos , Estructura Molecular , Piridinas/síntesis química , Ratas , Estilbenos/síntesis química
13.
Ther Adv Med Oncol ; 3(1): 11-25, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21789152

RESUMEN

Ixabepilone demonstrates marked synergistic activity in combination with capecitabine, which served as the rationale for the evaluation of this combination in the clinic. Ixabepilone plus capecitabine is currently approved for patients with locally advanced or metastatic breast cancer (MBC) progressing after treatment with an anthracycline and a taxane; approval was based on the results of two phase III trials comparing the combination with capecitabine monotherapy. An array of preclinical studies in multiple solid tumor types show that ixabepilone demonstrates therapeutic synergy with targeted therapies including trastuzumab, bevacizumab, brivanib, and cetuximab; with immune-modulating agents such as anti-CTLA-4 antibody; and with other chemotherapy drugs such as irinotecan and epirubicin. Notably, experiments in several xenograft models show that ixabepilone provides greater antitumor synergism when combined with bevacizumab than either paclitaxel or nab-paclitaxel combined with bevacizumab. These preclinical findings provide a foundation for ongoing phase II clinical trials using ixabepilone in combination with trastuzumab or lapatinib in HER2-positive breast cancer; with bevacizumab in breast cancer, endometrial cancer, renal cancer, and non-small cell lung cancer (NSCLC); with cetuximab in breast cancer, NSCLC, and pancreatic cancer; and with brivanib, dasatinib, sorafinib, sunitinib, or vorinostat in MBC. Preliminary results from several of these trials suggest that ixabepilone-based combinations have promising anticancer activity.

14.
Prostate ; 71(5): 480-8, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20878947

RESUMEN

BACKGROUND: Androgen receptor (AR) antagonists are part of the standard of care for prostate cancer. Despite the almost inevitable development of resistance in prostate tumors to AR antagonists, no new AR antagonists have been approved for over a decade. Treatment failure is due in part to mutations that increase activity of AR in response to lower ligand concentrations as well as to mutations that result in AR response to a broader range of ligands. The failure to discover new AR antagonists has occurred in the face of continued research; to enable progress, a clear understanding of the reasons for failure is required. METHODS: Non-clinical drug safety studies and safety pharmacology assays were performed on previously approved AR antagonists (bicalutamide, flutamide, nilutamide), next generation antagonists in clinical testing (MDV3100, BMS-641988), and a pre-clinical drug candidate (BMS-501949). In addition, non-clinical studies with AR mutant mice, and EEG recordings in rats were performed. Non-clinical findings are compared to disclosures of clinical trial results. RESULTS: As a drug class, AR antagonists cause seizure in animals by an off-target mechanism and are found in vitro to inhibit GABA-A currents. Clinical trials of candidate next generation AR antagonists identify seizure as a clinical safety risk. CONCLUSIONS: Non-clinical drug safety profiles of the AR antagonist drug class create a significant barrier to the identification of next generation AR antagonists. GABA-A inhibition is a common off-target activity of approved and next generation AR antagonists potentially explaining some side effects and safety hazards of this class of drugs.


Asunto(s)
Antagonistas de Andrógenos/farmacología , Antagonistas de Andrógenos/toxicidad , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/farmacocinética , Animales , Perros , Descubrimiento de Drogas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Neoplasias de la Próstata/metabolismo , Ratas , Ratas Sprague-Dawley
16.
Cancer Res ; 69(16): 6522-30, 2009 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-19654297

RESUMEN

Despite an excellent initial response to first-line hormonal treatment, most patients with metastatic prostate cancer will succumb to a hormone-refractory form of the disease. Because these tumors are still dependent on a functional androgen receptor (AR), there is a need to find novel and more potent antiandrogens. While searching for small molecules that bind to the AR and inhibit its transcriptional activity, BMS-641988 was discovered. This novel antiandrogen showed an increased (>1 log) potency compared with the standard antiandrogen, bicalutamide, in both binding affinity to the AR and inhibition of AR-mediated transactivation in cell-based reporter assays. In mature rats, BMS-641988 strongly inhibited androgen-dependent growth of the ventral prostate and seminal vesicles. In the CWR-22-BMSLD1 human prostate cancer xenograft model, BMS-641988 showed increased efficacy over bicalutamide (average percent tumor growth inhibition >90% versus <50%), even at exposure levels of bicalutamide 3-fold greater than what can be attained in humans. Furthermore, BMS-641988 was efficacious in CWR-22-BMSLD1 tumors initially refractory to treatment with bicalutamide. BMS-641988 was highly efficacious in the LuCaP 23.1 human prostate xenograft model, inducing stasis throughout the approximately 30-day dosing. To explore the functional mechanisms of BMS-641988, gene expression profiling analysis was done on CWR-22-BMSLD1 xenograft models in mice. Treatment with BMS-641988 resulted in a global gene expression profile more similar to castration compared with that of bicalutamide. Overall, these data highlight that the unique preclinical profile of BMS-641988 may provide additional understanding for the hormonal treatment of prostate cancer.


Asunto(s)
Antagonistas de Receptores Androgénicos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Imidas/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Antagonistas de Andrógenos/farmacología , Antagonistas de Andrógenos/uso terapéutico , Animales , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Descubrimiento de Drogas , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Imidas/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Biológicos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Bioorg Med Chem Lett ; 18(6): 1910-5, 2008 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-18291644

RESUMEN

A novel series of [2.2.1]-oxabicyclo imide-based compounds were identified as potent antagonists of the androgen receptor. Molecular modeling and iterative drug design were applied to optimize this series. The lead compound [3aS-(3aalpha,4beta,5beta,7beta,7aalpha)]-4-(octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile was shown to have potent in vivo efficacy after oral dosing in the CWR22 human prostate tumor xenograph model.


Asunto(s)
Antagonistas de Receptores Androgénicos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Isoindoles/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Administración Oral , Antagonistas de Andrógenos/farmacología , Anilidas/farmacología , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Cromatografía Líquida de Alta Presión , Diseño de Fármacos , Humanos , Isoindoles/síntesis química , Isoindoles/farmacocinética , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Nitrilos/farmacología , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Unión Proteica , Receptores Androgénicos/metabolismo , Relación Estructura-Actividad , Compuestos de Tosilo/farmacología , Células Tumorales Cultivadas
19.
Bioorg Med Chem Lett ; 18(2): 634-9, 2008 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-18055203

RESUMEN

2-Amino-5-(thioaryl)thiazoles are potent inhibitors of TrkA (e.g., 20h, TrkA IC(50)=0.6 nM) that show anti-proliferative effect in cellular assays. A proposed inhibitor binding mode to TrkA active site is consistent with key SAR observations.


Asunto(s)
Receptor trkA/antagonistas & inhibidores , Tiazoles/farmacología , Fosforilación , Receptor trkA/metabolismo , Relación Estructura-Actividad , Tiazoles/química
20.
J Med Chem ; 49(26): 7596-9, 2006 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-17181141

RESUMEN

A novel, N-aryl-bicyclohydantoin selective androgen receptor modulator scaffold was discovered through structure-guided modifications of androgen receptor antagonists. A prototype compound (7R,7aS)-10b from this series is a potent and highly tissue-selective agonist of the androgen receptor. After oral dosing in a rat atrophied levator ani muscle model, (7R,7aS)-10b demonstrated efficacy at restoring levator ani muscle mass to that of intact controls and exhibited >50-fold selectivity for muscle over prostate.


Asunto(s)
Hidrocarburos Aromáticos con Puentes/farmacología , Hidantoínas/farmacología , Músculo Esquelético/efectos de los fármacos , Atrofia Muscular/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Administración Oral , Animales , Neoplasias de la Mama/tratamiento farmacológico , Hidrocarburos Aromáticos con Puentes/síntesis química , Hidrocarburos Aromáticos con Puentes/química , Células Cultivadas , Dihidrotestosterona/farmacología , Humanos , Hidantoínas/administración & dosificación , Hidantoínas/síntesis química , Hidantoínas/química , Luciferasas/metabolismo , Masculino , Ratones , Músculo Esquelético/crecimiento & desarrollo , Mioblastos/efectos de los fármacos , Ratas , Activación Transcripcional
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