RESUMEN
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that serves as an important regulator of a broad range of cellular functions. It has been linked to Alzheimer's disease as well as various other diseases, including mood disorders, type 2 diabetes, and cancer. There is considerable evidence indicating that GSK-3ß in the central nervous system plays a role in the production of abnormal, hyperphosphorylated, microtubule-associated tau protein found in neurofibrillary tangles associated with Alzheimer's disease. A series of analogues containing a pyrimidine-based hinge-binding heterocycle was synthesized and evaluated, leading to the identification of highly potent GSK-3 inhibitors with excellent kinase selectivity. Further evaluation of 34 and 40 in vivo demonstrated that these compounds are orally bioavailable, brain-penetrant GSK-3 inhibitors that lowered levels of phosphorylated tau in a triple-transgenic mouse Alzheimer's disease model.
Asunto(s)
Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Ratones , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Proteínas tau/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Ratones Transgénicos , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , FosforilaciónRESUMEN
We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extra-terminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable in vitro profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (15), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when 15 was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of 15 in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses.
RESUMEN
Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.
Asunto(s)
Antineoplásicos/farmacología , Carbazoles/farmacología , Descubrimiento de Drogas , Fenilalanina/farmacología , Prolina/farmacología , Triptófano/farmacología , Administración Oral , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Carbazoles/administración & dosificación , Carbazoles/química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Fenilalanina/administración & dosificación , Fenilalanina/química , Prolina/administración & dosificación , Prolina/química , Relación Estructura-Actividad , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Triptófano/administración & dosificación , Triptófano/químicaRESUMEN
Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.
RESUMEN
JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.
RESUMEN
The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. Optimization for JAK family selectivity led to compounds 14 and 21, with greater than 45-fold selectivity for JAK2 over all other members of the JAK kinase family.
Asunto(s)
Amidas/química , Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Amidas/metabolismo , Amidas/farmacología , Sitios de Unión , Carbazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Janus Quinasa 2/metabolismo , Janus Quinasa 3/antagonistas & inhibidores , Janus Quinasa 3/metabolismo , Simulación de Dinámica Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
A novel series of 5-((4-aminopiperidin-1-yl)methyl)-pyrrolo[2,1-f][1,2,4]triazin-4-amines with small aniline substituents at the C4 position were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. Compound 8l exhibited promising oral efficacy in both EGFR and HER2-driven human tumor xenograft models.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Receptores ErbB/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Neoplasias/enzimología , Proteínas Tirosina Quinasas/farmacocinética , Proteínas Tirosina Quinasas/farmacología , Pirroles/química , Pirroles/farmacocinética , Pirroles/farmacología , Pirroles/uso terapéutico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Triazinas/química , Triazinas/farmacocinética , Triazinas/farmacología , Triazinas/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Biarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model.
Asunto(s)
Aminas/química , Aminopiridinas/síntesis química , Antineoplásicos/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Aminopiridinas/química , Aminopiridinas/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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
Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
Asunto(s)
Aminopiridinas/síntesis química , Antineoplásicos/síntesis química , Dihidropiridinas/síntesis química , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Piridonas/síntesis química , Administración Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Dihidropiridinas/farmacocinética , Dihidropiridinas/farmacología , Perros , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Piridonas/farmacocinética , Piridonas/farmacología , Ratas , Solubilidad , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.
Asunto(s)
Antineoplásicos/síntesis química , Fosfotransferasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Piridonas/farmacología , Receptores de Factores de Crecimiento/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas c-met , Piridonas/síntesis química , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidoresRESUMEN
A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors of Met kinase activity. The SAR at various positions of the two kinase scaffolds was investigated. These studies led to the discovery of compounds 3b and 20b, which demonstrated favorable pharmacokinetic properties in mice and significant antitumor activity in a human gastric carcinoma xenograft model.
Asunto(s)
Aminopiridinas/síntesis química , Aminopiridinas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirroles/síntesis química , Pirroles/farmacología , Urea/síntesis química , Urea/farmacología , Aminopiridinas/química , Animales , Humanos , Ratones , Inhibidores de Proteínas Quinasas/química , Pirroles/química , Neoplasias Gástricas/inducido químicamente , Neoplasias Gástricas/patología , Relación Estructura-Actividad , Urea/análogos & derivados , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pirroles/química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Receptores de Factores de Crecimiento/antagonistas & inhibidores , Neoplasias Gástricas/tratamiento farmacológico , Triazinas/química , Animales , Células CACO-2/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas/efectos de los fármacos , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Glutatión Transferasa/antagonistas & inhibidores , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Conformación Proteica , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-met , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores de Factores de Crecimiento/metabolismo , Neoplasias Gástricas/sangre , Neoplasias Gástricas/enzimología , Relación Estructura-ActividadRESUMEN
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/químicaRESUMEN
A novel structural class of p38 mitogen-activated protein (MAP) kinase inhibitors consisting of substituted 4-(phenylamino)-pyrrolo[2,1- f][1,2,4]triazines has been discovered. An initial subdeck screen revealed that the oxindole-pyrrolo[2,1- f][1,2,4]triazine lead 2a displayed potent enzyme inhibition (IC 50 60 nM) and was active in a cell-based TNFalpha biosynthesis inhibition assay (IC 50 210 nM). Replacement of the C4 oxindole with 2-methyl-5- N-methoxybenzamide aniline 9 gave a compound with superior p38 kinase inhibition (IC 50 10 nM) and moderately improved functional inhibition in THP-1 cells. Further replacement of the C6 ester of the pyrrolo[2,1- f][1,2,4]triazine with amides afforded compounds with increased potency, excellent oral bioavailability, and robust efficacy in a murine model of acute inflammation (murine LPS-TNFalpha). In rodent disease models of chronic inflammation, multiple compounds demonstrated significant inhibition of disease progression leading to the advancement of 2 compounds 11b and 11j into further preclinical and toxicological studies.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Pirroles/síntesis química , Triazinas/síntesis química , Administración Oral , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Femenino , Humanos , Técnicas In Vitro , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Proteína Quinasa 14 Activada por Mitógenos/química , Modelos Moleculares , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Ratas Endogámicas Lew , Relación Estructura-Actividad , Triazinas/farmacocinética , Triazinas/farmacología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.
Asunto(s)
Química Farmacéutica/métodos , Receptores ErbB/química , Neoplasias/tratamiento farmacológico , Piperidinas/síntesis química , Pirroles/síntesis química , Receptor ErbB-2/química , Triazinas/síntesis química , Adenosina Trifosfato/metabolismo , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Insectos , Modelos Químicos , Trasplante de Neoplasias , Piperidinas/química , Piperidinas/farmacología , Pirroles/química , Pirroles/farmacología , Triazinas/química , Triazinas/farmacologíaRESUMEN
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
Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the ribose phosphate portion of the ATP binding pocket.
Asunto(s)
Química Farmacéutica/métodos , Receptores ErbB/antagonistas & inhibidores , Pirroles/síntesis química , Receptor ErbB-2/antagonistas & inhibidores , Triazinas/síntesis química , Adenosina Trifosfato/química , Animales , Células CACO-2 , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Trasplante de Neoplasias , Fosfatos/química , Pirroles/farmacología , Ribosa/química , Triazinas/farmacologíaRESUMEN
Chronic myeloid leukemia (CML) is caused by the constitutively activated tyrosine kinase breakpoint cluster (BCR)-ABL. Current frontline therapy for CML is imatinib, an inhibitor of BCR-ABL. Although imatinib has a high rate of clinical success in early phase CML, treatment resistance is problematic, particularly in later stages of the disease, and is frequently mediated by mutations in BCR-ABL. Dasatinib (BMS-354825) is a multitargeted tyrosine kinase inhibitor that targets oncogenic pathways and is a more potent inhibitor than imatinib against wild-type BCR-ABL. It has also shown preclinical activity against all but one of the imatinib-resistant BCR-ABL mutants tested to date. Analysis of the crystal structure of dasatinib-bound ABL kinase suggests that the increased binding affinity of dasatinib over imatinib is at least partially due to its ability to recognize multiple states of BCR-ABL. The structure also provides an explanation for the activity of dasatinib against imatinib-resistant BCR-ABL mutants.