RESUMEN
OBJECTIVE: Stents have evolved through three generations, the latest of which are totally bioresorbable to include drugs targeting restenosis, the surface polymer eluting those drugs, and scaffolds on which those drugs are coated. These scaffolds, however, thus far, have been pharmacologically inactive and remain a potential site for delivering a second drug. Therefore, we sought to evaluate the possibility of modifying a bioresorbable polymer so that it can double as a scaffold for both a stent and a drug targeting impaired re-endothelialization and stent thrombosis. METHODS AND RESULTS: We successfully modified a standard bioresorbable terpolymer in a way found to be consistent with the covalent incorporation of lovastatin, as seen on NMR, into a backbone comprised of lactide, glycolide, ε-caprolactone, and lovastatin (60 : 15 : 10 : 15 parts by weight), respectively. This was accomplished through a reaction of the four components of the polymer at 100°C for 18 h in the presence of an alcohol initiator and a scandium catalyst. The resulting terpolymer was fabricated into a scaffold using a novel RSF system developed by 3D Biotek. CONCLUSION: It preliminarily appears feasible to fabricate a fourth-generation bioresorbable stent that has the potential to deliver two drugs to the site of the procedure-related vessel lumen injury.
Asunto(s)
Implantes Absorbibles , Portadores de Fármacos , Stents Liberadores de Fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Lovastatina/administración & dosificación , Polímeros/síntesis química , Espectroscopía de Resonancia Magnética , Ensayo de Materiales , Diseño de PrótesisRESUMEN
The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAF(V600E) results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRAF(V600E) inhibitors. In particular, the bioisosteric replacement of a metabolically sensitive tert-butyl group with fluorinated alkyl moieties is described. This effort led directly to the identification of a clinical candidate, compound 40 (CEP-32496). Compound 40 exhibits high potency against several BRAF(V600E)-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAF(V600E) versus those containing wild-type BRAF. Compound 40 also exhibits an excellent PK profile across multiple preclinical species. In addition, significant oral efficacy was observed in a 14-day BRAF(V600E)-dependent human Colo-205 tumor xenograft mouse model, upon dosing at 30 and 100 mg/kg BID.
Asunto(s)
Isoxazoles/síntesis química , Compuestos de Fenilurea/síntesis química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Quinazolinas/síntesis química , Administración Oral , Animales , Unión Competitiva , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Perros , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Isoxazoles/farmacocinética , Isoxazoles/farmacología , Macaca fascicularis , Masculino , Ratones , Ratones Desnudos , Microsomas Hepáticos , Modelos Moleculares , Mutación , Trasplante de Neoplasias , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
Aryl phenyl ureas with a 4-quinazolinoxy substituent at the meta-position of the phenyl ring are potent inhibitors of mutant and wild type BRAF kinase. Compound 7 (1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea hydrochloride) exhibits good pharmacokinetic properties in rat and mouse and is efficacious in a mouse tumor xenograft model following oral dosing.
Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismo , Quinazolinas/farmacología , Urea/farmacología , Animales , Relación Dosis-Respuesta a Droga , Ratones , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Quinazolinas/síntesis química , Quinazolinas/química , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Distribución Tisular , Urea/análogos & derivados , Urea/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Treatment of AML patients with small molecule inhibitors of FLT3 kinase has been explored as a viable therapy. However, these agents are found to be less than optimal for the treatment of AML because of lack of sufficient potency or suboptimal oral pharmacokinetics (PK) or lack of adequate tolerability at efficacious doses. We have developed a series of extremely potent and highly selective FLT3 inhibitors with good oral PK properties. The first series of compounds represented by 1 (AB530) was found to be a potent and selective FLT3 kinase inhibitor with good PK properties. The aqueous solubility and oral PK properties at higher doses in rodents were found to be less than optimal for clinical development. A novel series of compounds were designed lacking the carboxamide group of 1 with an added water solubilizing group. Compound 7 (AC220) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models. Compound 7 has demonstrated a desirable safety and PK profile in humans and is currently in phase II clinical trials.
Asunto(s)
Benzotiazoles/farmacología , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Benzotiazoles/síntesis química , Benzotiazoles/química , Benzotiazoles/farmacocinética , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Masculino , Ratones , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacocinética , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Solubilidad , Especificidad por Sustrato , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Activating mutations in the receptor tyrosine kinase FLT3 are present in up to approximately 30% of acute myeloid leukemia (AML) patients, implicating FLT3 as a driver of the disease and therefore as a target for therapy. We report the characterization of AC220, a second-generation FLT3 inhibitor, and a comparison of AC220 with the first-generation FLT3 inhibitors CEP-701, MLN-518, PKC-412, sorafenib, and sunitinib. AC220 exhibits low nanomolar potency in biochemical and cellular assays and exceptional kinase selectivity, and in animal models is efficacious at doses as low as 1 mg/kg given orally once daily. The data reveal that the combination of excellent potency, selectivity, and pharmacokinetic properties is unique to AC220, which therefore is the first drug candidate with a profile that matches the characteristics desirable for a clinical FLT3 inhibitor.
Asunto(s)
Benzotiazoles/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Bencenosulfonatos/farmacología , Benzotiazoles/farmacocinética , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Carbazoles/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Furanos , Humanos , Ratones , Ratones Desnudos , Ratones SCID , Niacinamida/análogos & derivados , Compuestos de Fenilurea/farmacocinética , Fosforilación/efectos de los fármacos , Piperazinas/farmacología , Pronóstico , Mapeo de Interacción de Proteínas , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Piridinas/farmacología , Quinazolinas/farmacología , Sorafenib , Estaurosporina/análogos & derivados , Estaurosporina/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of diaryl ureas with an amide substitution at the 4-position was prepared and found to be potent and selective FLT3 inhibitors with good oral bioavailability and efficacy in a tumor xenograft model.
Asunto(s)
Antineoplásicos/química , Urea/análogos & derivados , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Humanos , Ratones , Ratones Desnudos , Relación Estructura-Actividad , Urea/síntesis química , Urea/farmacocinética , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
The structure-based design, synthesis, and biological activity of a novel indazole-containing inhibitor series for S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Use of 5-aminoindazole as the core scaffold provided a structure-guided series of low nanomolar inhibitors with broad-spectrum antimicrobial activity. The implementation of structure-based methodologies provided a 6000-fold increase in potency over a short timeline (several months) and an economy of synthesized compounds.