RESUMEN
Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (25), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity. BIIB129 (25) demonstrated efficacy in disease-relevant preclinical in vivo models of B cell proliferation in the CNS, exhibits a favorable safety profile suitable for clinical development as an immunomodulating therapy for MS, and has a low projected total human daily dose.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa , Encéfalo , Esclerosis Múltiple , Inhibidores de Proteínas Quinasas , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Esclerosis Múltiple/tratamiento farmacológico , Humanos , Animales , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/química , Encéfalo/metabolismo , Ratones , Descubrimiento de Drogas , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Ratas , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , FemeninoRESUMEN
INTRODUCTION: Tyrosine kinase 2 (TYK2) is a member of the JAK family class of kinases that is responsible for mediating the immune response to IL-12, IL-23, and IFNα. The therapeutic value of targeting this pathway in autoimmune diseases is supported by human genetics and multiple companies are developing small-molecule inhibitors as potential new treatments. AREAS COVERED: This article seeks to give a comprehensive review of the applications related to selective small-molecule TYK2 inhibition since the last publication in this journal in 2019. Recent regulatory activity, emerging clinical data, and new companies entering the clinic with selective TYK2 inhibitors will also be discussed. EXPERT OPINION: Over the past 3 years there has been an increase in the number of companies and patent applications claiming selective TYK2 inhibitors. Deucravacitinib, an allosteric TYK2 inhibitor discovered by BMS, is the most advanced molecule in clinical development and in 2021, it received positive phase 3 data for the treatment of plaque psoriasis. . This development has spurred a renewed interest in targeting TYK2 with selective inhibitors and several new molecules have recently entered phase 1 trials. The research interest in this area is likely to further increase as additional clinical data with deucravacitinib and other TYK2 inhibitors continue to emerge.
Asunto(s)
Enfermedades Autoinmunes , Inhibidores de Proteínas Quinasas , Psoriasis , TYK2 Quinasa/antagonistas & inhibidores , Enfermedades Autoinmunes/tratamiento farmacológico , Humanos , Patentes como Asunto , Inhibidores de Proteínas Quinasas/uso terapéutico , Psoriasis/tratamiento farmacológicoRESUMEN
The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11ß-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Benzamidas/química , Inhibidores Enzimáticos/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Administración Oral , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Sitios de Unión , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Macaca fascicularis , Microsomas Hepáticos/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Apoptosis signal-regulating kinase 1 (ASK1) is one of the key mediators of the cellular stress response that regulates inflammation and apoptosis. To probe the therapeutic value of modulating this pathway in preclinical models of neurological disease, we further optimized the profile of our previously reported inhibitor 3. This effort led to the discovery of 32, a potent (cell IC50 = 25 nM) and selective ASK1 inhibitor with suitable pharmacokinetic and brain penetration (rat Cl/Clu = 1.6/56 L/h/kg and Kp,uu = 0.46) for proof-of-pharmacology studies. Specifically, the ability of 32 to inhibit ASK1 in the central nervous system (CNS) was evaluated in a human tau transgenic (Tg4510) mouse model exhibiting elevated brain inflammation. In this study, transgenic animals treated with 32 (at 3, 10, and 30 mg/kg, BID/PO for 4 days) showed a robust reduction of inflammatory markers (e.g., IL-1ß) in the cortex, thus confirming inhibition of ASK1 in the CNS.
Asunto(s)
Encéfalo/efectos de los fármacos , Descubrimiento de Drogas , Inflamación/tratamiento farmacológico , MAP Quinasa Quinasa Quinasa 5/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Animales , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Inflamación/metabolismo , MAP Quinasa Quinasa Quinasa 5/metabolismo , Ratones , Ratones Transgénicos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Ratas , Relación Estructura-ActividadRESUMEN
Apoptosis signal-regulating kinase 1 (ASK1) is a key mediator in the apoptotic and inflammatory cellular stress response. To investigate the therapeutic value of modulating this pathway in neurological disease, we have completed medicinal chemistry studies to identify novel CNS-penetrant ASK1 inhibitors starting from peripherally restricted compounds reported in the literature. This effort led to the discovery of 21, a novel ASK1 inhibitor with good potency (cell IC50 = 138 nM), low clearance (rat Cl/Clu = 0.36/6.7 L h-1 kg-1) and good CNS penetration (rat K p,uu = 0.38).
RESUMEN
Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Quinolinas/farmacología , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piridinas/síntesis química , Piridinas/química , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.
Asunto(s)
Adenosina/farmacología , Enfermedades Autoinmunes/prevención & control , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Inflamación/prevención & control , Inhibidores de Proteínas Quinasas/farmacología , Quinolinas/farmacología , Adenosina/química , Adenosina/metabolismo , Animales , Células Cultivadas , Fosfatidilinositol 3-Quinasa Clase I/química , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Transgénicos , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Quinolinas/química , Quinolinas/metabolismo , Ratas Endogámicas Lew , Células Sf9 , Relación Estructura-ActividadRESUMEN
We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
Asunto(s)
Acetatos/farmacología , Antineoplásicos/farmacología , Piperidonas/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Acetatos/química , Administración Oral , Antineoplásicos/química , Disponibilidad Biológica , Cristalografía por Rayos X , Descubrimiento de Drogas , Humanos , Piperidonas/química , Conformación ProteicaRESUMEN
Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 µM. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 µM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21(WAF1) mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Animales , Dicroismo Circular , Cristalografía , Cristalografía por Rayos X , Diseño de Fármacos , Femenino , Humanos , Indicadores y Reactivos , Ratones , Ratones Desnudos , Modelos Moleculares , Morfolinas/síntesis química , Morfolinas/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.
Asunto(s)
Acetatos/síntesis química , Antineoplásicos/síntesis química , Piperidonas/síntesis química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Acetatos/farmacocinética , Acetatos/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Hepatocitos/metabolismo , Humanos , Macaca fascicularis , Ratones , Ratones Desnudos , Modelos Moleculares , Conformación Molecular , Trasplante de Neoplasias , Piperidonas/farmacocinética , Piperidonas/farmacología , Unión Proteica , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Trasplante Heterólogo , Proteínas de Unión al GTP rho/biosíntesisRESUMEN
Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kß/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kß and δ isoforms in the treatment of a number of inflammatory diseases.
Asunto(s)
Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Modelos MolecularesRESUMEN
Prostaglandin D2 (PGD2) plays a key role in mediating allergic reactions seen in asthma, allergic rhinitis, and atopic dermatitis. PGD2 exerts its activity through two G protein-coupled receptors (GPCRs), prostanoid D receptor (DP or DP1), and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2). We report the optimization of a series of phenylacetic acid derivatives in an effort to improve the dual activity of AMG 009 against DP and CRTH2. These efforts led to the discovery of AMG 853 (2-(4-(4-(tert-butylcarbamoyl)-2-(2-chloro-4-cyclopropylphenyl sulfonamido)phenoxy)-5-chloro-2-fluorophenyl)acetic acid), which is being evaluated in human clinical trials for asthma.
RESUMEN
A simple, scalable, and efficient one-pot methodology for the synthesis of 4,4-disubstituted cyclohexane beta-keto esters from benzylic nitriles or esters and methyl acrylate promoted by potassium tert-butoxide is described. The process relies on a tandem double Michael addition-Dieckmann condensation reaction, which results in the formation of three discrete carbon-carbon bonds in a single pot, including a quaternary center. The method allows for the convenient and rapid synthesis of a variety of 4-aryl-4-cyano-2-carbomethoxycyclohexanone and 4-aryl-2,4-biscarbomethoxycyclohexanone building blocks for use in natural products synthesis and medicinal chemistry.
Asunto(s)
Ciclohexanonas/química , Ésteres/químicaRESUMEN
Synthetic approaches to the furanocembrane family of natural products, e.g. lophotoxins, pukalides, bipinnatins, based on: i) an intramolecular cyclisation of an alpha,beta-unsaturated acyl radical intermediate into a conjugated enone, and ii) an intramolecular Stille coupling reaction involving a 2-stannylfuran and a vinyl iodide, are described. A total synthesis of bis-deoxylophotoxin , the probable biological precursor to the neurotoxin lophotoxin, isolated from species of the Pacific sea whip Lophogorgia, is then presented.
Asunto(s)
Diterpenos/síntesis química , Furanos/química , Ciclización , Diterpenos/química , Furanos/síntesis química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
A novel approach toward the synthesis of the BCD ring system of penitrem D is described. The strategy capitalizes on the fast cyclization rates of aryl radicals into cyclobutenes and allows access to a variety of fused tricyclic structures. Radical/polar crossover reactions of precursors 24-29 promoted by samarium diiodide in the presence of HMPA and acetone allow access to the fully functionalized BCD ring system of penitrem D. The stereochemical implications of these processes are evaluated, and a Pd-mediated cyclization approach toward the penitrems is also introduced.