RESUMEN
The (Z)-fluoro-olefin amide bioisosteric replacement is an effective tool for addressing various shortcomings of the parent amide. In an effort to fine tune ADME properties of BACE1 preclinical candidate AM-6494, a series of structurally distinct (Z)-fluoro-olefin containing analogs was developed that culminated in compound 15. Herein, we detail design considerations, synthetic challenges, structure activity relationship (SAR) studies, and in vivo properties of an advanced compound in this novel series of BACE1 inhibitors.
Asunto(s)
Alquenos/farmacología , Amidas/farmacología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Desarrollo de Medicamentos , Inhibidores Enzimáticos/farmacología , Hidrocarburos Fluorados/farmacología , Alquenos/síntesis química , Alquenos/química , Amidas/síntesis química , Amidas/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Células HEK293 , Humanos , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/química , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A nonracemic synthesis of the glucokinase-glucokinase regulatory protein disruptor AMG-3969 (5) is reported. Key features of the synthetic approach are an asymmetric synthesis of the 2-alkynyl piperazine core via a base-promoted isomerization and a revised approach to the synthesis of the aminopyridinesulfonamide with an improved safety profile.
Asunto(s)
Compuestos de Bencilo/síntesis química , Carbamatos/síntesis química , Proteínas Portadoras/antagonistas & inhibidores , Piperazinas/síntesis química , Piridinas/síntesis química , Sulfonamidas/síntesis química , Compuestos de Bencilo/química , Carbamatos/química , Proteínas Portadoras/química , Indicadores y Reactivos/química , Isomerismo , Estructura Molecular , Piperazinas/química , Piridinas/química , Sulfonamidas/químicaRESUMEN
Chromosomal instability (CIN) is a hallmark of cancer, caused by persistent errors in chromosome segregation during mitosis. Aggressive cancers like high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) have a high frequency of CIN and TP53 mutations. Here, we show that inhibitors of the KIF18A motor protein activate the mitotic checkpoint and selectively kill chromosomally unstable cancer cells. Sensitivity to KIF18A inhibition is enriched in TP53-mutant HGSOC and TNBC cell lines with CIN features, including in a subset of CCNE1-amplified, CDK4-CDK6-inhibitor-resistant and BRCA1-altered cell line models. Our KIF18A inhibitors have minimal detrimental effects on human bone marrow cells in culture, distinct from other anti-mitotic agents. In mice, inhibition of KIF18A leads to robust anti-cancer effects with tumor regression observed in human HGSOC and TNBC models at well-tolerated doses. Collectively, our results provide a rational therapeutic strategy for selective targeting of CIN cancers via KIF18A inhibition.
Asunto(s)
Cinesinas , Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Cinesinas/genética , Cinesinas/metabolismo , Mitosis/genética , Línea Celular , Puntos de Control de la Fase M del Ciclo CelularRESUMEN
A series of aminooxadiazoles was optimized for inhibition of Cdc7. Early lead isoquinoline 1 suffered from modest cell potency (cellular IC50=0.71 µM measuring pMCM2), low selectivity against structurally related kinases, and high IV clearance in rats (CL=18 L/h/kg). Extensive optimization resulted in azaindole 26 (Cdc7 IC50=1.1 nM, pMCM2 IC50=32 nM) that demonstrated robust lowering of pMCM2 in a mouse pharmacodynamic (PD) model when dosed orally. Modifications to improve the pharmacokinetic profile of this series were guided by trapping experiments with glutathione in rat hepatocytes.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Oxadiazoles/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Desnudos , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Chromosomal instability (CIN) is a hallmark of cancer that results from errors in chromosome segregation during mitosis. Targeting of CIN-associated vulnerabilities is an emerging therapeutic strategy in drug development. KIF18A, a mitotic kinesin, has been shown to play a role in maintaining bipolar spindle integrity and promotes viability of CIN cancer cells. To explore the potential of KIF18A, a series of inhibitors was identified. Optimization of an initial hit led to the discovery of analogues that could be used as chemical probes to interrogate the role of KIF18A inhibition. Compounds 23 and 24 caused significant mitotic arrest in vivo, which was sustained for 24 h. This would be followed by cell death either in mitosis or in the subsequent interphase. Furthermore, photoaffinity labeling experiments reveal that this series of inhibitors binds at the interface of KIF18A and tubulin. This study represents the first disclosure of KIF18A inhibitors with in vivo activity.
Asunto(s)
Cinesinas , Neoplasias , Muerte Celular , Humanos , Mitosis , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Huso Acromático/metabolismo , Tubulina (Proteína)/metabolismoRESUMEN
A 2-aminothiazole derivative 1 was developed as a potential inhibitor of the oncology target AKT, a serine/threonine kinase. When incubated in rat and human liver microsomes in the presence of NADPH, 1 underwent significant metabolic activation on its 2-aminothiazole ring, leading to substantial covalent protein binding. Upon addition of glutathione, covalent binding was reduced significantly, and multiple glutathione adducts were detected. Novel metabolites from the in vitro incubates were characterized by LC-MS and NMR to discern the mechanism of bioactivation. An in silico model was developed based on the proposed mechanism and was employed to predict bioactivation in 23 structural analogues. The predictions were confirmed empirically for the bioactivation liability, in vitro, by LC-MS methods screening for glutathione incorporation. New compounds were identified with a low propensity for bioactivation.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Glutatión/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Tiazoles/efectos adversos , Tiazoles/química , Animales , Compuestos Epoxi/metabolismo , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Biológicos , Estructura Molecular , Ratas , Tiazoles/metabolismoRESUMEN
A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis. Key compounds showed activity in cellular assays measuring phosphorylation of two AKT substrates, PRAS40 and FKHRL1. Compound 30 was advanced to a mouse liver PD assay, where it showed dose-dependent inhibition of AKT activity, as measured by the inhibition of phospho-PRAS40.
Asunto(s)
Antineoplásicos/química , Isoquinolinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Tiadiazoles/química , Tiazoles/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Dominio Catalítico , Cristalografía por Rayos X , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Isoquinolinas/síntesis química , Isoquinolinas/farmacocinética , Ratones , Neoplasias/tratamiento farmacológico , Fosforilación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/farmacocinética , Tiazoles/síntesis química , Tiazoles/farmacocinéticaRESUMEN
Through a combination of screening and structure-based rational design, we have discovered a series of N(1)-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma.
Asunto(s)
Antineoplásicos/química , Azoles/química , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Azoles/farmacocinética , Azoles/uso terapéutico , Sitios de Unión , Cristalografía por Rayos X , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Diseño de Fármacos , Ratones , Ratones Desnudos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
ß-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartyl protease that plays a key role in the production of amyloid ß (Aß) in the brain and has been extensively pursued as a target for the treatment of Alzheimer's disease (AD). BACE2, an aspartyl protease that is structurally related to BACE1, has been recently reported to be involved in melanosome maturation and pigmentation. Herein, we describe the development of a series of cyclopropylthiazines as potent and orally efficacious BACE1 inhibitors. Lead optimization led to the identification of 20, a molecule with biochemical IC50 BACE2/BACE1 ratio of 47. Administration of 20 resulted in no skin/fur color change in a 13-day mouse hypopigmentation study and demonstrated robust and sustained reduction of CSF and brain Aß40 levels in rat and monkey pharmacodynamic models. On the basis of a compelling data package, 20 (AM-6494) was advanced to preclinical development.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ciclopropanos/farmacología , Inhibidores Enzimáticos/farmacología , Tiazinas/farmacología , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ciclopropanos/química , Ciclopropanos/farmacocinética , Ciclopropanos/uso terapéutico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Humanos , Masculino , Ratones , Modelos Moleculares , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/metabolismo , Ratas Sprague-Dawley , Tiazinas/química , Tiazinas/farmacocinética , Tiazinas/uso terapéuticoRESUMEN
[reaction: see text] A series of 4-alkyl-5-aminoisoxazoles have been synthesized in high yield by nucleophilic addition of lithiated alkyl nitriles to (alpha)-chlorooximes. The scope and limitations of this reaction were examined by varying the nature of the nitrile and chloride oxime.
Asunto(s)
Aminas/síntesis química , Isoxazoles/síntesis química , Nitrilos/química , Alquilación , Aminas/química , Catálisis , Técnicas Químicas Combinatorias , Isoxazoles/química , OximasRESUMEN
The development of acetyl-CoA carboxylase (ACC) inhibitors for the treatment of metabolic disease has been pursued by the pharmaceutical industry for some time. A number of recent disclosures describing potent ACC inhibitors have been reported by multiple research groups. Unlike many prior publications in this area, more recent publications contain a significant amount of in vivo efficacy data generated by long-term experiments in rodent models of metabolic disease. Additionally, one compound has been advanced to human clinical studies. The results from these studies should allow researchers to better gauge the potential utility of ACC inhibition for the treatment of human disease.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Inhibidores Enzimáticos/uso terapéutico , Enfermedades Metabólicas/tratamiento farmacológico , Acetil-CoA Carboxilasa/química , Animales , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK-GKRP disrupters are revealed. Diarylmethanesulfonamide hit 6 (hGK-hGKRP IC50 = 1.2 µM) was optimized to lead compound 32 (AMG-0696; hGK-hGKRP IC50 = 0.0038 µM). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (nN â σ*S-X) in 32 was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound 32 was shown to induce GK translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = -45%; 100 mg/kg po, 3 h). X-ray analyses of 32 and several precursors bound to GKRP were also obtained. This novel disrupter of GK-GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Glucoquinasa/metabolismo , Hipoglucemiantes/química , Sulfonamidas/química , Tiofenos/química , Transporte Activo de Núcleo Celular , Animales , Glucemia/metabolismo , Núcleo Celular/metabolismo , Cristalografía por Rayos X , Citoplasma/metabolismo , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Conformación Molecular , Unión Proteica , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Tiofenos/farmacocinética , Tiofenos/farmacologíaRESUMEN
[reaction: see text] Applications of methodology for the synthesis of propargylic alcohols related to polyketide natural products were examined. Noyori's asymmetric transfer hydrogenation of alpha-chiral alkynones was found to be highly selective and catalyst controlled. Additions of TMS acetylene to alpha-chiral aldehydes, catalyzed by a Ti(O-i-Pr)(4)-BINOL complex, were diastereoselective but substrate dependent.
Asunto(s)
Alcoholes/síntesis química , Macrólidos/química , Organofosfatos/química , Pargilina/química , Pironas/química , Acetileno/química , Aldehídos/química , Alquinos/química , Catálisis , Hidrogenación , Estructura Molecular , Compuestos Organometálicos/química , Rutenio/químicaRESUMEN
[formula: see text] An improved route to the polypropionate segment of callystatin A is described in which the efficient directed hydrostannation of an internal alkyne and subsequent iodinolysis provides a key vinylic iodide intermediate.
Asunto(s)
Ácidos Grasos Insaturados/síntesis química , Alquinos/química , Antineoplásicos/síntesis química , Estaño/químicaRESUMEN
We report the identification of a PDE10A clinical candidate by optimizing potency and in vivo efficacy of promising keto-benzimidazole leads 1 and 2. Significant increase in biochemical potency was observed when the saturated rings on morpholine 1 and N-acetyl piperazine 2 were changed by a single atom to tetrahydropyran 3 and N-acetyl piperidine 5. A second single atom modification from pyrazines 3 and 5 to pyridines 4 and 6 improved the inhibitory activity of 4 but not 6. In the in vivo LC-MS/MS target occupancy (TO) study at 10 mg/kg, 3, 5, and 6 achieved 86-91% occupancy of PDE10A in the brain. Furthermore, both CNS TO and efficacy in PCP-LMA behavioral model were observed in a dose dependent manner. With superior in vivo TO, in vivo efficacy and in vivo PK profiles in multiple preclinical species, compound 5 (AMG 579) was advanced as our PDE10A clinical candidate.
Asunto(s)
Antipsicóticos/química , Bencimidazoles/química , Inhibidores de Fosfodiesterasa/química , Hidrolasas Diéster Fosfóricas/metabolismo , Pirazinas/química , Administración Oral , Animales , Antipsicóticos/síntesis química , Antipsicóticos/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Disponibilidad Biológica , Encéfalo/metabolismo , Perros , Humanos , Masculino , Actividad Motora/efectos de los fármacos , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/química , Primates , Conformación Proteica , Pirazinas/síntesis química , Pirazinas/farmacología , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Acetyl-CoA carboxylase (ACC) is a target of interest for the treatment of metabolic syndrome. Starting from a biphenyloxadiazole screening hit, a series of piperazine oxadiazole ACC inhibitors was developed. Initial pharmacokinetic liabilities of the piperazine oxadiazoles were overcome by blocking predicted sites of metabolism, resulting in compounds with suitable properties for further in vivo studies. Compound 26 was shown to inhibit malonyl-CoA production in an in vivo pharmacodynamic assay and was advanced to a long-term efficacy study. Prolonged dosing with compound 26 resulted in impaired glucose tolerance in diet-induced obese (DIO) C57BL6 mice, an unexpected finding.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Oxadiazoles/farmacología , Piperazinas/farmacología , Acetil-CoA Carboxilasa/metabolismo , Animales , Dieta/efectos adversos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Piperazinas/síntesis química , Piperazinas/química , Relación Estructura-ActividadRESUMEN
Tumor protein 53 (p53) is a critical regulator of cell cycle and apoptosis that is frequently disabled in human tumors. In many tumor types, p53 is deleted or mutated, but in others p53 is inactivated by overexpression or amplification of its negative regulator mouse double minute 2 (MDM2). A high-throughput screening effort identified 6,7-bis(4-bromophenyl)-7,12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine as a potent inhibitor of the MDM2-p53 protein-protein interaction. This screening hit was found to be chemically unstable and difficult to handle due to poor DMSO solubility. Co-crystallization with the target protein helped to direct further optimization and provided a tractable lead series of novel MDM2-p53 inhibitors. In cellular assays, these compounds were shown to upregulate p53 protein levels and p53 signaling and to cause p53-dependent inhibition of proliferation and apoptosis.
Asunto(s)
Descubrimiento de Drogas , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Pirimidinas/química , Pirimidinas/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células HCT116 , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Conformación Molecular , Unión Proteica/efectos de los fármacos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Four stereoisomeric hybrids of the polyketide natural products callystatin A and leptomycin B have been prepared by parallel synthetic routes involving chiral allenylstannane methodology. Like their natural counterparts, these hybrids exhibit nanomolar levels of cytotoxicity toward HCT-116 human colon cancer cells.
Asunto(s)
Ácidos Grasos Insaturados/síntesis química , Ácidos Grasos Insaturados/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Ácidos Grasos Insaturados/química , Humanos , Conformación Molecular , EstereoisomerismoRESUMEN
A total synthesis of the cytotoxic polyketide marine natural product callystatin A is described. The route features chiral allenylmetal additions to construct the polypropionate C15-22 segment and an sp(2)-sp(3) Suzuki coupling to join the C1-C11 and C12-C22 subunits.