RESUMEN
ABBV-467 is a highly potent and selective MCL-1 inhibitor that was advanced to a phase I clinical trial for the treatment of multiple myeloma. Due to its large size and structural complexity, ABBV-467 is a challenging synthetic target. Herein, we describe the synthesis of ABBV-467 on a decagram scale, which enabled preclinical characterization. The strategy is convergent and stereoselective, featuring a hindered biaryl cross coupling, enantioselective hydrogenation, and conformationally preorganized macrocyclization by C-O bond formation as key steps.
Asunto(s)
Antineoplásicos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Antineoplásicos/farmacología , Hidrogenación , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidoresRESUMEN
We herein report an enantioselective bioreduction of ketones that bear the most frequently used nitrogen-heteroaromatics in FDA-approved drugs. Ten varieties of these nitrogen-containing heterocycles were systematically investigated. Eight categories were studied for the first time and seven types were tolerated, significantly expanding the substrate scope of plant-mediated reduction. By use of purple carrots in buffered aqueous media with a simplified reaction setup, this biocatalytic transformation was achieved within 48 h at ambient temperature, offering medicinal chemists a pragmatic and scalable tool to access a broad variety of nitrogen-heteroaryl-containing chiral alcohols. With multiple reactive sites, the structurally diverse set of chiral alcohols can be used for library compound preparation, early route-scouting activities, and synthesis of other pharmaceutical molecules, favorably accelerating medicinal chemistry campaigns.
RESUMEN
BACKGROUND: MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902). METHODS: Binding of ABBV-467 to human MCL-1 was assessed in multiple cell lines. The ability of ABBV-467 to induce tumor growth inhibition was investigated in xenograft models of human multiple myeloma and acute myelogenous leukemia. The first-in-human study was a multicenter, open-label, dose-escalation study assessing safety, pharmacokinetics, and efficacy of ABBV-467 monotherapy. RESULTS: Here we show that administration of ABBV-467 to MCL-1-dependent tumor cell lines triggers rapid and mechanism-based apoptosis. In vivo, intermittent dosing of ABBV-467 as monotherapy or in combination with venetoclax inhibits the growth of xenografts from human hematologic cancers. Results from a clinical trial evaluating ABBV-467 in patients with multiple myeloma based on these preclinical data indicate that treatment with ABBV-467 can result in disease control (seen in 1 patient), but may also cause increases in cardiac troponin levels in the plasma in some patients (seen in 4 of 8 patients), without other corresponding cardiac findings. CONCLUSIONS: The selectivity of ABBV-467 suggests that treatment-induced troponin release is a consequence of MCL-1 inhibition and therefore may represent a class effect of MCL-1 inhibitors in human patients.
Apoptosis is a type of cell death that removes abnormal cells from the body. Cancer cells can have increased levels of MCL-1, a protein that helps cells survive and prevents apoptosis. ABBV-467 is a new drug that blocks the action of MCL-1 (an MCL-1 inhibitor) and could promote apoptosis. In animal models, ABBV-467 led to cancer cell death and delayed tumor growth. ABBV-467 was also studied in a clinical trial in 8 patients with multiple myeloma, a blood cancer. In 1 patient, ABBV-467 treatment prevented the cancer from getting any worse for 8 months. However, in 4 out of 8 patients ABBV-467 increased the levels of troponin, a protein associated with damage to the heart. This concerning side effect may impact the future development of MCL-1 inhibitors as anticancer drugs.
RESUMEN
BCL-XL, an antiapoptotic member of the BCL-2 family of proteins, drives tumor survival and maintenance and thus represents a key target for cancer treatment. Herein we report the rational design of a novel series of selective BCL-XL inhibitors exemplified by A-1293102. This molecule contains structural elements of selective BCL-XL inhibitor A-1155463 and the dual BCL-XL/BCL-2 inhibitors ABT-737 and navitoclax, while representing a distinct pharmacophore as assessed by an objective cheminformatic evaluation. A-1293102 exhibited picomolar binding affinity to BCL-XL and both efficiently and selectively killed BCL-XL-dependent tumor cells. X-ray crystallographic analysis demonstrated a key hydrogen bonding network in the P2 binding pocket of BCL-XL, while the bent-back moiety achieved efficient occupancy of the P4 pocket in a manner similar to that of navitoclax. A-1293102 represents one of the few distinct structural series of selective BCL-XL inhibitors, and thus serves as a useful tool for biological studies as well as a lead compound for further optimization.
RESUMEN
Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-XL inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp3-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-XL. A-1331852 has since been used as a critical tool molecule for further exploring BCL-2 family protein biology, while also representing an attractive entry into a drug discovery program.
RESUMEN
A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Cicloheptanos/síntesis química , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Hipolipemiantes/síntesis química , Cetoácidos/síntesis química , Urea/análogos & derivados , Urea/síntesis química , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacocinética , Compuestos de Bifenilo/farmacología , Cicloheptanos/farmacocinética , Cicloheptanos/farmacología , Diacilglicerol O-Acetiltransferasa/genética , Ingestión de Alimentos/efectos de los fármacos , Humanos , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacología , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Cetoácidos/farmacocinética , Cetoácidos/farmacología , Hígado/metabolismo , Ratones , Ratones Mutantes , Estereoisomerismo , Relación Estructura-Actividad , Triglicéridos/metabolismo , Urea/farmacocinética , Urea/farmacología , Pérdida de PesoRESUMEN
Herein we report a concise protocol for the diastereoselective synthesis of novel bridged bicyclic lactams from commercially available components by the sequence of Ugi, ring-closing metathesis (RCM), and Heck reactions. X-ray diffraction studies revealed that the bicyclic products contain varying degrees of pyramidalization of the bridgehead nitrogen atom.
Asunto(s)
Lactamas/síntesis química , Cristalografía por Rayos X , Ciclización , Lactamas/química , Modelos Moleculares , Estructura Molecular , EstereoisomerismoRESUMEN
An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor 1 (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (>40 microM) and brain (>20 microg/g) with <15% change in cardiovascular endpoints. As a result of these stringent requirements, lead optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHr1 antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Sistema Cardiovascular/efectos de los fármacos , Cromonas/síntesis química , Piperidinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/efectos adversos , Fármacos Antiobesidad/sangre , Presión Sanguínea/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular Tumoral , Cromonas/efectos adversos , Cromonas/sangre , Perros , Indazoles/efectos adversos , Indazoles/sangre , Indazoles/síntesis química , Masculino , Ratones , Ratones Endogámicos C57BL , Contracción Miocárdica/efectos de los fármacos , Piperidinas/efectos adversos , Piperidinas/sangre , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Distribución TisularRESUMEN
Dipeptidyl peptidase IV (DPP4) deactivates glucose-regulating hormones such as GLP-1 and GIP, thus, DPP4 inhibition has become a useful therapy for type 2 diabetes. Optimization of the high-throughput screening lead 6 led to the discovery of 25 (ABT-341), a highly potent, selective, and orally bioavailable DPP4 inhibitor. When dosed orally, 25 dose-dependently reduced glucose excursion in ZDF rats. Amide 25 is safe in a battery of in vitro and in vivo tests and may represent a new therapeutic agent for the treatment of type 2 diabetes.
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Compuestos de Bifenilo/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/metabolismo , Hipoglucemiantes/farmacología , Inhibidores de Serina Proteinasa/farmacología , Triazoles/farmacología , Animales , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacocinética , Ciclohexenos/química , Diabetes Mellitus Tipo 2/genética , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Femenino , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Modelos Moleculares , Ratas , Ratas Zucker , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/farmacocinética , Difracción de Rayos XRESUMEN
Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonists in an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series as having excellent safety against the chosen cardiovascular endpoints at high drug concentrations in the plasma and brain. Optimization of this series led to considerable improvements in affinity, functional potency, and pharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that was orally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat, and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascular model compared to other series reported by our group. However, this analogue also led to prolongation of the QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functional blockade of this ion channel.
Asunto(s)
Benzodioxoles/farmacología , Enfermedades Cardiovasculares/inducido químicamente , Cromonas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Acilación , Animales , Área Bajo la Curva , Benzodioxoles/farmacocinética , Benzodioxoles/toxicidad , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Calcio/metabolismo , Línea Celular , Cromonas/farmacocinética , Cromonas/toxicidad , Perros , Electrocardiografía/efectos de los fármacos , Femenino , Semivida , Frecuencia Cardíaca/efectos de los fármacos , Indicadores y Reactivos , Ratones , Ratones Endogámicos C57BL , Canales de Potasio/efectos de los fármacos , Canales de Potasio/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Optimization of a high-throughput screening hit against melanin-concentrating hormone receptor 1 (MCHr1) led to the discovery of 2-(4-benzyloxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide (7a). This compound was found to be a high-affinity ligand for MCHr1 and a potent inhibitor of MCH-mediated Ca(2+) release, showed good plasma and CNS exposure upon oral dosing in diet-induced obese mice, and is the first reported MCHr1 antagonist that is efficacious upon oral dosing in a chronic model of weight loss.
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Acetamidas/síntesis química , Fármacos Antiobesidad/síntesis química , Indazoles/síntesis química , Obesidad/tratamiento farmacológico , Pirrolidinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Acetamidas/farmacocinética , Acetamidas/farmacología , Administración Oral , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/farmacología , Unión Competitiva , Encéfalo/metabolismo , Calcio/metabolismo , Enfermedad Crónica , Indazoles/farmacocinética , Indazoles/farmacología , Ratones , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Ensayo de Unión Radioligante , Relación Estructura-Actividad , Distribución TisularRESUMEN
4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evaluation of 7 in an anesthetized dog model of cardiovascular safety revealed adverse hemodynamic effects at a plasma concentration comparable to the minimally effective therapeutic concentration. These results highlight the need for scrutiny of the cardiovascular safety profile of MCHr1 antagonists.
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Cumarinas/síntesis química , Piperidinas/síntesis química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Receptores de Somatostatina/antagonistas & inhibidores , Administración Oral , Animales , Fármacos Antiobesidad/efectos adversos , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Disponibilidad Biológica , Presión Sanguínea/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular Tumoral , Cumarinas/efectos adversos , Cumarinas/farmacología , Perros , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético , Humanos , Masculino , Ratones , Ratones Obesos , Contracción Miocárdica/efectos de los fármacos , Piperidinas/efectos adversos , Piperidinas/farmacología , Ensayo de Unión Radioligante , Relación Estructura-ActividadRESUMEN
Several novel cascade processes have been designed and developed that involve sequential reactions of imines and iminium ions to form substituted quinolizidine ring systems in a single step from simple and readily available starting materials. The utility and promise of these cascade reactions is evident from their application to extraordinarily concise syntheses of the representative quinolizidine alkaloids (+/-)-epilupinine and (-)-epimyrtine.
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Alcaloides/síntesis química , Iminas/química , Quinazolinas/síntesis química , Esparteína/análogos & derivados , Alcaloides/análisis , Estructura Molecular , Quinazolinas/análisis , Esparteína/análisis , Esparteína/síntesis química , EstereoisomerismoRESUMEN
A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Pirazoles/síntesis química , Pirimidinas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Células CACO-2 , Bases de Datos Factuales , Diacilglicerol O-Acetiltransferasa/química , Perros , Femenino , Hurones , Tránsito Gastrointestinal/efectos de los fármacos , Células HeLa , Hemodinámica/efectos de los fármacos , Humanos , Hiperlipidemias/sangre , Hiperlipidemias/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Periodo Posprandial , Pirazoles/farmacocinética , Pirazoles/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Relación Estructura-Actividad , Triglicéridos/sangre , Vómitos/inducido químicamenteRESUMEN
BACKGROUND: Postprandial hypertriglyceridemia has been identified as a major independent risk factor for future cardiovascular events. Therefore, inhibition of triglyceride synthesis has enormous therapeutic potential in the treatment of metabolic disorders. Diacylglycerol acyltransferase (DGAT) enzymes catalyze the final and only committed step in triglyceride biosynthesis and have thus been identified as potential therapeutic targets to combat human cardio-metabolic diseases. OBJECTIVE/METHOD: Significant interest in DGAT-1 inhibitors has emerged in the last several years. To provide a perspective on the exciting features of this enzyme for targeting metabolic diseases, a summary of the biology and pharmacology surrounding the DGAT enzymes is presented. Following this is a discussion of the various chemotypes that have been disclosed within relevant patent applications published in 2008. Specifically, the similarities and differences of the chemical structures and the biological data that are provided to support the corresponding claims are presented. CONCLUSION: Small molecule and biologic-based DGAT inhibitors have been successfully used for the preclinical validation of DGAT enzymes as targets for the treatment of metabolic diseases. Given the advanced stage in which some of the chemical matter resides, it is expected that DGAT inhibitors will enter the clinic in the coming years.
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Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Sistemas de Liberación de Medicamentos , Inhibidores Enzimáticos/farmacología , Animales , Productos Biológicos/farmacología , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/prevención & control , Diseño de Fármacos , Humanos , Hipertrigliceridemia/complicaciones , Hipertrigliceridemia/tratamiento farmacológico , Enfermedades Metabólicas/fisiopatología , Enfermedades Metabólicas/prevención & control , Patentes como Asunto , Factores de RiesgoRESUMEN
The discovery of small molecule melanin concentrating hormone receptor (MHCr1) antagonists as novel therapeutic agents has been widely pursued across the pharmaceutical industry. While multiple chemotypes of small molecule MCHr1 antagonists have been identified and shown to induce weight loss in rodent models of obesity, many of these lead compounds have been found to cross react with the hERG channel. This review describes efforts that led to the identification of two sub-series of MCHr1 antagonists with low affinity for the hERG channel. Ultimately, however, the modifications introduced to thwart hERG channel activity resulted in lead compounds with sub-optimal CNS behavior.
Asunto(s)
Canales de Potasio Éter-A-Go-Go/metabolismo , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Animales , Sistema Cardiovascular/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Unión Proteica , Receptores de la Hormona Hipofisaria/metabolismoRESUMEN
The discovery of small molecule melanin concentrating hormone receptor (MCHr1) antagonists as novel therapeutic agents for the treatment of obesity has been actively pursued across the pharmaceutical industry. While multiple chemotypes of small molecule MCHr1 antagonists have been identified and shown to deliver weight loss in animal models of obesity, many of these lead compounds have been found to cross-react with the hERG channel and/or demonstrate deleterious effects on cardiovascular hemodynamic parameters. This review describes an approach to rapidly identifying safer MCHr1 antagonists by placing assays to assess cardiovascular safety early in the lead optimization compound prioritization process. Ultimately, despite putting significant effort toward the discovery of a MCHr1 antagonist for the treatment of obesity, we were unable to deliver a candidate compound that attained an acceptable therapeutic index (TI = 30-100) in our in vivo models. Our inability to identify a compound with an acceptable therapeutic index was driven by two primary factors: 1) high levels of sustained drug exposure in the brain was required to achieve efficacy; and 2) many small molecule MCHR1 receptor antagonists suffer from receptor cross-reactivity that leads to cardiovascular toxicity at low multiples of their therapeutic plasma concentration.
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Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Receptores de la Hormona Hipofisaria/metabolismo , Amidas/química , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Sensibilidad y Especificidad , Relación Estructura-ActividadRESUMEN
AMP-activated protein kinase (AMPK) is well established as a sensor and regulator of intracellular and whole-body energy metabolism. A high-throughput screen was performed in order to identify chemotypes that are bound by AMPK. A novel thienopyridone compound (1) was identified and subsequently optimized. The structure-activity relationships that emerged from this effort are described.
Asunto(s)
Metabolismo Energético/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Activadores de Enzimas/farmacología , Complejos Multienzimáticos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Piridinas/farmacología , Proteínas Quinasas Activadas por AMP , Bioensayo , Metabolismo Energético/fisiología , Activación Enzimática/fisiología , Activadores de Enzimas/química , Piridinas/química , Relación Estructura-ActividadRESUMEN
The optimization of potent MCHr1 antagonist 1 with respect to improving its in vitro profile by replacement of the 3,4-methylenedioxy phenyl (piperonyl) moiety led to the discovery of 19, a compound that showed excellent MCHr1 binding and functional potencies in addition to possessing superior hERG separation, CYP3A4 profile, and receptor cross-reactivity profiles.