RESUMEN
Therapeutic development of a targeted agent involves a series of decisions over additional activities that may be ignored, eliminated or pursued. This paper details the concurrent application of two methods that provide a spectrum of information about the biological activity of a compound: biochemical profiling on a large panel of kinase assays and transcriptional profiling of mRNA responses. Our mRNA profiling studies used a full dose range, identifying subsets of transcriptional responses with differing EC(50)s which may reflect distinct targets. Profiling data allowed prioritization for validation in xenograft models, generated testable hypotheses for active compounds, and informed decisions on the general utility of the series.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/genética , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Quinasa 9 Dependiente de la Ciclina/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor IGF Tipo 1/genética , TriajeRESUMEN
Pyrrolidine, pyrrolidinone, carbocyclic, and acyclic groups were used as isosteric proline replacements in a series of insulin-like growth factor I receptor kinase/insulin receptor kinase inhibitors. Examples that were similar in potency to proline-containing reference compounds were shown to project a key fluoropyridine amide into a common space, while less potent compounds were not able to do so for reasons of stereochemistry or structural rigidity.
Asunto(s)
Prolina/química , Inhibidores de Proteínas Quinasas/química , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor de Insulina/antagonistas & inhibidores , Triazinas/química , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacología , Triazinas/farmacologíaRESUMEN
A series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.
Asunto(s)
Bencimidazoles/química , Piperazinas/química , Inhibidores de Proteínas Quinasas/química , Piridonas/química , Administración Oral , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Humanos , Ratones , Ratones Desnudos , Piperazinas/síntesis química , Piperazinas/farmacocinética , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Piridonas/síntesis química , Piridonas/farmacocinética , Piridonas/farmacología , Ratas , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The SAR of PXR transactivation by 3-(benzimidazol-2-yl)-pyridine-2-one based ATP competitive inhibitors of Insulin-like Growth Factor 1 Receptor kinase (IGF-1R) is discussed. Compounds without PXR transactivation, with in vivo antitumor activity, reduced protein binding and improved oral exposure are presented.
Asunto(s)
Antineoplásicos/química , Bencimidazoles/química , Inhibidores de Proteínas Quinasas/química , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptores de Esteroides/genética , Activación Transcripcional , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Línea Celular Tumoral , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Humanos , Ratones , Ratones Desnudos , Receptor X de Pregnano , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Receptor IGF Tipo 1/metabolismo , Receptores de Esteroides/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
3-(Benzimidazol-2-yl)-pyridine-2-one-based ATP competitive inhibitors of Insulin-like Growth Factor 1 Kinase (IGF-IR) were optimized for reduced Cyp3A4 inhibition and improved oral exposure. The use of malonate as methyl anion synthon via S(N)Ar reaction and double decarboxylation under mild conditions is demonstrated.
Asunto(s)
Bencimidazoles/farmacología , Inhibidores del Citocromo P-450 CYP3A , Receptor IGF Tipo 1/antagonistas & inhibidores , Adenosina Trifosfato/química , Administración Oral , Área Bajo la Curva , Química Farmacéutica/métodos , Citocromo P-450 CYP3A/química , Diseño de Fármacos , Flúor/química , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Nitrógeno/química , Receptor IGF Tipo 1/química , Somatomedinas/química , Timidina/químicaRESUMEN
A series of IGF-1R inhibitors is disclosed, wherein the (m-chlorophenyl)ethanol side chain of BMS-536924 (1) is replaced with a series of 2-(1H-imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chains. Some analogs show improved IGF-1R potency and oral exposure. Analogs from both series, 16a and 17f, show in vivo activity comparable to 1 in our constitutively activated IGF-1R Sal tumor model. This may be the due to the improved protein binding in human and mouse serum for imidazole 16a and the excellent oral exposure of pyrazole 17f.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Piridonas/química , Piridonas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Humanos , Ratones , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Unión Proteica , Suero , Relación Estructura-ActividadRESUMEN
A series of fluoroglycosylated fluoroindolocarbazoles was examined with respect to their topoisomerase I activity, cytotoxicity, and selectivity. The lead clinical candidate from this series, BMS-250749, displays broad spectrum antitumor activity superior to CPT-11 against some preclinical xenograft models, including curative antitumor activity against Lewis lung carcinoma.
Asunto(s)
Antineoplásicos/síntesis química , Camptotecina/análogos & derivados , Camptotecina/farmacología , Carbazoles/síntesis química , Glucósidos/síntesis química , Indoles/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Carbazoles/química , Carbazoles/farmacología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Glucósidos/química , Glucósidos/farmacología , Humanos , Técnicas In Vitro , Indoles/química , Indoles/farmacología , Irinotecán , Ratones , Microsomas Hepáticos/metabolismo , Inhibidores de Topoisomerasa I , Trasplante HeterólogoRESUMEN
Compound 3 (BMS-536924), a novel small-molecule inhibitor of the insulin-like growth factor receptor kinase with equal potency against the insulin receptor is described. The in vitro and in vivo biological activity of this interesting compound is also reported.
Asunto(s)
Antineoplásicos/síntesis química , Bencimidazoles/síntesis química , Piridinas/síntesis química , Piridonas/síntesis química , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Haplorrinos , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Trasplante de Neoplasias , Piridinas/química , Piridinas/farmacología , Piridonas/química , Piridonas/farmacología , Ratas , Receptor de Insulina/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
[reaction: see text] Both 6'- and 4'-fluoro-glycosylated indolo[2,3-a]carbazoles are substrates for base-induced loss of fluorine as a leaving group from sp3 carbon. In the case of alpha-N-glycosylated substrate 3, loss of fluorine from the 6'-position leads to 3,6-anhydroglucose analogue 1. A novel N12,N13-bridged sugar analogue 2 results from loss of 4'-fluorine from beta-N-glycosylated analogue 4. Both analogues 1 and 2 display topo I inhibitory potencies similar to camptothecin.
Asunto(s)
Carbazoles/síntesis química , Carbono/química , Inhibidores Enzimáticos/síntesis química , Flúor/química , Glicósidos/síntesis química , Compuestos Heterocíclicos de Anillo en Puente/síntesis química , Hidrocarburos Fluorados/síntesis química , Indoles/síntesis química , Inhibidores de Topoisomerasa I , Animales , Carbazoles/farmacología , Inhibidores Enzimáticos/farmacología , Glicósidos/farmacología , Compuestos Heterocíclicos de Anillo en Puente/farmacología , Hidrocarburos Fluorados/química , Indoles/química , Leucemia P388 , Conformación Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A fermentation directed product search for potential anticancer drugs conducted by Bristol-Myers in the 1970s and early 1980s resulted in the identification of a novel indolocarbazole (IC) rebeccamycin (RBM) as a potential drug development candidate. Subsequently, an analog program designed to impart distal site in vivo antitumor activity resulted in the discovery of diethylaminoethyl analog of RBM (DEAE-RBM), which is presently undergoing clinical evaluation as NSC 655649 and BMY-27557. Strong DNA intercalation is the primary mechanism of action of DEAE-RBM resulting in the potent catalytic inhibition of both topoisomerases I and II. Precursor feeding fermentation experiments with fluorine-substituted tryptophans yielded novel fluoroindolocarbazoles (FICs). These FICs were identified as targeting topoisomerase (topo) I in a mechanism-based screen and their action on topo I was confirmed by production of topo I-mediated single-strand breaks in DNA at sites essentially identical to those induced by camptothecin. Topo I dependent cytotoxicity was demonstrated for specific FICs using a P388 and camptothecin-resistant P388/CPT45 pair of cell lines, the latter expresses little or no functional topo I. For example, topo I selectivity was greatest with 3,9-difluoro substituted FIC and was least significant and least cytotoxic with 4,8-difluoro substituted FIC. The review focuses on the discovery of the rebeccamycin class of compounds and their structure-activity relationships leading to the development of the clinical candidate BMY-27557 (NSC 655649), as well as the lead identification of the fluoroindolocarbazole class of compounds.
Asunto(s)
Aminoglicósidos , Antibacterianos/farmacología , Antibióticos Antineoplásicos/farmacología , Carbazoles/farmacología , Indoles/farmacología , Animales , Antibacterianos/síntesis química , Antibióticos Antineoplásicos/síntesis química , Carbazoles/síntesis química , Diseño de Fármacos , Glucósidos , Humanos , Indoles/síntesis química , Neoplasias/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.
Asunto(s)
Antineoplásicos/síntesis química , Carbazoles/síntesis química , Glucósidos/síntesis química , Neoplasias de la Próstata/tratamiento farmacológico , Inhibidores de Topoisomerasa I , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Carbazoles/química , Carbazoles/farmacología , Glucósidos/química , Glucósidos/farmacología , Masculino , Ratones , Trasplante de Neoplasias , Solubilidad , Relación Estructura-Actividad , Agua , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Generation of imino-quinone methide type intermediates from 2-aminothiazole-5-carbinols using alkylsulfonic acids in nitromethane followed by trapping with a wide range of nucleophiles effects C-C, C-O, C-N, C-S, and C-P bond formation.
Asunto(s)
Iminas/química , Indolquinonas/síntesis química , Metanol/análogos & derivados , Tiazoles/química , Indolquinonas/química , Metanol/química , Estructura Molecular , EstereoisomerismoRESUMEN
BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC50, 5-365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.
Asunto(s)
Pirazoles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor de Insulina/antagonistas & inhibidores , Triazinas/farmacología , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Western Blotting , Caspasa 3/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cetuximab , Relación Dosis-Respuesta a Droga , Prueba de Tolerancia a la Glucosa , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Desnudos , Estructura Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Pirazoles/administración & dosificación , Pirazoles/farmacocinética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Triazinas/administración & dosificación , Triazinas/farmacocinética , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.
Asunto(s)
Investigación Biomédica , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Triazinas/farmacología , Animales , Perros , Descubrimiento de Drogas , Humanos , Ratones , Modelos Moleculares , Conformación Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/química , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Ratas , Receptor IGF Tipo 1/química , Relación Estructura-Actividad , Triazinas/química , Triazinas/farmacocinética , Triazinas/uso terapéuticoRESUMEN
Structure-activity relationships in a series of 4-[1H-indazol-5-ylamino]pyrrolo[2,1-f][1,2,4]triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with excellent biochemical potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626) was selected as a clinical candidate for treatment of solid tumors.
Asunto(s)
Antineoplásicos/síntesis química , Carbamatos/síntesis química , Receptores ErbB/antagonistas & inhibidores , Receptor ErbB-2/antagonistas & inhibidores , Triazinas/síntesis química , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Carbamatos/farmacocinética , Carbamatos/farmacología , Línea Celular Tumoral , Perros , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Macaca fascicularis , Ratones , Trasplante de Neoplasias , Estereoisomerismo , Relación Estructura-Actividad , Trasplante Heterólogo , Triazinas/farmacocinética , Triazinas/farmacologíaRESUMEN
We previously reported that 1 (BMS-536924), a benzimidazole inhibitor of the insulin-like growth factor-1 receptor, had demonstrated in vivo antitumor activity. This lead compound was found to have potent CYP3A4 inhibition, CYP3A4 induction mediated by PXR transactivation, poor aqueous solubility, and high plasma protein binding. Herein we disclose the evolution of this chemotype to address these issues. This effort led to 10 (BMS-695735), which exhibits improved ADME properties, a low risk for drug-drug interactions, and in vivo efficacy in multiple xenograft models.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacología , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Piridonas/administración & dosificación , Piridonas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/química , Bencimidazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Desnudos , Estructura Molecular , Trasplante de Neoplasias , Receptor X de Pregnano , Inhibidores de Proteínas Quinasas/química , Piridonas/química , Receptores de Esteroides/efectos de los fármacos , Receptores de Esteroides/metabolismo , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor receptor-1 (IGF-1R) were examined in which the pendant imidazole moiety was replaced to improve selectivity for IGF-1R inhibition over cytochrome P450 (CYP). Synthesis and SAR of these compounds is presented.
Asunto(s)
Inhibidores Enzimáticos del Citocromo P-450 , Imidazoles/química , Imidazoles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Sistema Enzimático del Citocromo P-450/análisis , Imidazoles/síntesis química , Concentración 50 Inhibidora , Relación Estructura-ActividadRESUMEN
Novel C-5 aminomethyl pyrrolotriazines were prepared and optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The homopiperazine, 1p, emerged as a key lead and it showed promising oral efficacy in EGFR and dual EGFR/HER2 driven human tumor xenograft models. It is hypothesized that the C-5 homopiperazine side chain binds in the ribose-phosphate portion of the ATP binding pocket.
Asunto(s)
Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Metilaminas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirroles/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Triazinas/farmacología , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Metilaminas/química , Ratones , Modelos Moleculares , Estructura Molecular , Trasplante de Neoplasias , Pirroles/química , Relación Estructura-Actividad , Triazinas/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The discovery and synthesis of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor 1-receptor (IGF-1R) are presented. Installing amine containing side chains at the 4-position of pyridone ring significantly improved the enzyme potency. SAR and biological activity of these compounds is presented.
Asunto(s)
Piridinas/síntesis química , Piridinas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Bencimidazoles , Línea Celular , Humanos , Concentración 50 Inhibidora , Piridonas , Relación Estructura-ActividadRESUMEN
The identification of a potent series of IKK-beta selective inhibitors based on an imidazothienopyrazine template and the oral efficacy of one such analog (22j) in the LPS-induced TNF-alpha release mouse model are described.