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1.
Clin Cancer Res ; 12(24): 7444-55, 2006 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-17189418

RESUMEN

PURPOSE: The angiogenic phenotype of malignant cancers has been established as a target for cancer therapy. ABT-526 and ABT-510, two peptide mimetics of thrombospondin-1 (TSP-1), block angiogenesis in vitro and in vivo and slow tumor growth in mice. To guide the clinical development of these drugs, translational studies in dogs with naturally occurring cancers were initiated. EXPERIMENTAL DESIGN: A prospective open-label trial using ABT-510 or ABT-526 in pet dogs with measurable malignant spontaneously arising tumors. Endpoints included safety, pharmacokinetics, antitumor activity, and preliminary assessment of changes in circulating endothelial cell populations. RESULTS: Two-hundred and forty-two dogs were sequentially entered to this open-label trial. The elimination half-life for ABT-510 and ABT-526 was 0.7 and 0.8 h, respectively (range, 0.5-1 h). No dose-limiting toxicities were seen in any dogs (N = 242). Forty-two dogs receiving peptide had objective responses (>50% reduction in tumor size; n = 6) or significant disease stabilization. Most objective responses were seen after 60 days of exposure to the TSP-1 peptide. Antitumor activity was similar for both peptides and was seen in several histologies, including mammary carcinoma, head and neck carcinoma, soft tissue sarcoma, cutaneous T-cell lymphoma, and non-Hodgkin's lymphoma. Assessment of circulating endothelial cell populations in a small subset of dogs suggested that effective exposure to TSP-1 peptides may be associated with reductions in circulating endothelial cells. CONCLUSIONS: These results support the safety and activity of ABT-526 and ABT-510 in dogs with naturally occurring malignant cancers. Data from this preclinical trial support the development of TSP-1 mimetic peptides as anticancer agents.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Trombospondina 1/uso terapéutico , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/sangre , Inhibidores de la Angiogénesis/farmacología , Animales , Movimiento Celular/efectos de los fármacos , Perros , Ensayos de Selección de Medicamentos Antitumorales , Células Endoteliales/efectos de los fármacos , Femenino , Humanos , Masculino , Oligopéptidos/efectos adversos , Oligopéptidos/sangre , Oligopéptidos/farmacología , Fragmentos de Péptidos/efectos adversos , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/farmacología , Trombospondina 1/efectos adversos , Trombospondina 1/agonistas , Trombospondina 1/sangre , Trombospondina 1/farmacología , Células Tumorales Cultivadas
2.
J Med Chem ; 48(8): 2838-46, 2005 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-15828822

RESUMEN

The heptapeptide 1, NAc-Gly-Val-DIle-Thr-Arg-Ile-ArgNHEt, a structurally modified fragment derived from the second type-1 repeat of thrombospondin-1 (TSP-1), is known to possess antiangiogenic activity. However, therapeutic utility could not be demonstrated because this peptide has a very short half-life in rodents. To optimize the PD/PK profile of 1, we initiated a systematic SAR study. The initial structural modifications were performed at positions 5 and 7 of peptide 1 and at the N- and C-termini. Out of several hundred peptides synthesized, the nonapeptide 5 (ABT-526) emerged as a promising lead. ABT-526 inhibited VEGF-induced HMVEC cell migration and tube formation in the nanomolar range and increased apoptosis of HUAEC cells. ABT-526 showed acceptable PK in rodents, dog, and monkey. ABT-526, when incorporated in an angiogenic pellet implanted in the rat cornea at 10 microM, reduced neovascularization by 92%. Substitution of DalloIle in place of DIle in ABT-526 provided nonapeptide 6 (ABT-510), which was 30-fold less active than ABT-526 in the EC migration but 20-fold more active in the tube formation assay. In comparison to ABT-526, ABT-510 has increased water solubility and slower clearance in dog and monkey. Radiolabeled ABT-510 demonstrated saturable binding to HMVEC cells at 0.02-20 nM concentrations and was displaceable by TSP-1. ABT-510 and ABT-526 were shown to significantly increase apoptosis of HUAEC cells. ABT-510 was effective in blocking neovascularization in the mouse Matrigel plug model and inhibited tumor growth in the mouse Lewis lung carcinoma model. Previous studies had shown that ABT-510 was effective in inhibiting the outgrowth of murine melanoma metastases in syngeneic mice and in blocking the growth of human bladder carcinoma implanted in nude mice. It had been also shown that ABT-510 could regress tumor lesions in pet dogs or cause unexpected stabilization of the disease in advanced canine cancer. ABT-526 and ABT-510 are the first compounds in the class of potent inhibitors of angiogenesis that mimic the antiangiogenic function of TSP-1. ABT-510 is currently in phase II clinical studies.


Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Oligopéptidos/síntesis química , Trombospondina 1/química , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Apoptosis , Capilares/citología , Quimiotaxis/efectos de los fármacos , Córnea/irrigación sanguínea , Córnea/efectos de los fármacos , Perros , Células Endoteliales/efectos de los fármacos , Células Endoteliales/fisiología , Endotelio Vascular/citología , Femenino , Haplorrinos , Humanos , Técnicas In Vitro , Inyecciones Intravenosas , Ratones , Ratones Endogámicos C57BL , Imitación Molecular , Neovascularización Fisiológica/efectos de los fármacos , Oligopéptidos/farmacocinética , Oligopéptidos/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Cordón Umbilical/citología , Ensayos Antitumor por Modelo de Xenoinjerto
3.
J Org Chem ; 69(21): 7058-65, 2004 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-15471453

RESUMEN

4,5-Diaryl-1H-pyrazole-3-ol was utilized as a versatile template to synthesize several classes of compounds such as pyrazolo-oxazines 7, pyrazolo-benzooxazines 9, pyrazolo-oxazoles 10, and its analogues 11a-c as potential COX-2 inhibitors. Compounds 11b,c were successfully synthesized with use of pyridinium p-toluenesulfonate mediated cyclization of the ketal intermediate. Diaryl-pyrazolo-benzooxazepine analogues were synthesized by using Cu-mediated cyclization of the O-alkylated arylbromide intermediate. Arylsulfonamides were synthesized efficiently on a large scale with 4-[4-(4-fluorophenyl)-5-hydroxy-2H-pyrazol-3-yl]benzenesulfonamide 31 template readily synthesized from commercially available 4-sulfamoyl benzoic acid 29. The structure of a representative compound from each class was confirmed by X-ray crystallography. Selected compounds tested for inhibitory activity against COX-1 and COX-2 enzymes showed good selectivity for COX-2 versus COX-1 enzyme.


Asunto(s)
Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/farmacología , Isoenzimas/antagonistas & inhibidores , Pirazoles/síntesis química , Pirazoles/farmacología , Cristalografía por Rayos X , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Estructura Molecular , Prostaglandina-Endoperóxido Sintasas
4.
J Pharmacol Exp Ther ; 311(3): 904-12, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15277581

RESUMEN

Nonsteriodal anti-inflammatory drugs (NSAIDs) are efficacious for the treatment of pain associated with inflammatory disease. Clinical experience with marketed selective cyclooxygenase-2 (COX-2) inhibitors (celecoxib, rofecoxib, and valdecoxib) has confirmed the utility of these agents in the treatment of inflammatory pain with an improved gastrointestinal safety profile relative to NSAID comparators. These COX-2 inhibitors belong to the same structural class. Each contains a core heterocyclic ring with two appropriately substituted phenyl rings appended to adjacent atoms. Here, we report the identification of vicinally disubstituted pyridazinones as potent and selective COX-2 inhibitors. The lead compound in the series, ABT-963 [2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], has excellent selectivity (ratio of 276, COX-2/COX-1) in human whole blood, improved aqueous solubility compared with celecoxib and rofecoxib, high oral anti-inflammatory potency in vivo, and gastric safety in the animal studies. After oral administration, ABT-963 reduced prostaglandin E2 production in the rat carrageenan air pouch model (ED50 of 0.4 mg/kg) and reduced the edema in the carrageenan induced paw edema model with an ED30 of 1.9 mg/kg. ABT-963 dose dependently reduced nociception in the carrageenan hyperalgesia model (ED50 of 3.1 mg/kg). After 14 days of dosing in the adjuvant arthritis model, ABT-963 had an ED(50) of 1.0 mg/kg in reducing the swelling of the hind paws. Magnetic resonance imaging examination of the diseased paws in the adjuvant model showed that ABT-963 significantly reduced bone loss and soft tissue destruction. ABT-963 is a highly selective COX-2 inhibitor that may have utility in the treatment of the pain and inflammation associated with arthritis.


Asunto(s)
Artritis Experimental/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/farmacología , Isoenzimas/antagonistas & inhibidores , Piridazinas/farmacología , Sulfonas/farmacología , Animales , Plaquetas/efectos de los fármacos , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/fisiopatología , Carragenina , Enfermedades del Sistema Nervioso Central/inducido químicamente , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/sangre , Inhibidores de la Ciclooxigenasa/química , Perros , Edema/inducido químicamente , Edema/prevención & control , Eicosanoides/sangre , Calor , Hiperalgesia/tratamiento farmacológico , Interleucina-1/metabolismo , Masculino , Prostaglandina-Endoperóxido Sintasas , Prostaglandinas/biosíntesis , Prostaglandinas/sangre , Piridazinas/sangre , Piridazinas/química , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Receptores de Droga/efectos de los fármacos , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/patología , Sulfonas/sangre , Sulfonas/química
5.
Bioorg Med Chem Lett ; 14(4): 965-6, 2004 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-15013002

RESUMEN

Kringle 5, a proteolytic fragment of human plasminogen has been shown to potently inhibit angiogenesis. The tetrapeptide KLYD derived from kringle 5 has been shown to capture many activities of kringle 5 in vitro. Further simplification has been achieved by replacement of the two central amino acids with a 4-aminobenzoic acid spacer group. Molecules displaying the required recognition groups on this core show similar in vitro properties to kringle 5, and are able to displace radiolabeled protein from a high affinity binding site on endothelial cells.


Asunto(s)
Ácido 4-Aminobenzoico/química , Kringles , Imitación Molecular , Plasminógeno/farmacología , para-Aminobenzoatos , Inhibición de Migración Celular , Movimiento Celular/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Humanos , Estructura Molecular , Plasminógeno/química , Plasminógeno/genética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/farmacología
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