RESUMEN
Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Imidazoles/química , Inhibidores de Proteínas Quinasas/química , Pirazinas/química , Agammaglobulinemia Tirosina Quinasa/metabolismo , Animales , Artritis Experimental/tratamiento farmacológico , Sitios de Unión , Compuestos Bicíclicos con Puentes/química , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Semivida , Humanos , Imidazoles/metabolismo , Imidazoles/uso terapéutico , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/metabolismo , Pirazinas/uso terapéutico , Ratas , Ratas Wistar , Relación Estructura-Actividad , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/metabolismoRESUMEN
We report herein the design and synthesis of a series of orally active, liver-targeted hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors for the treatment of anemia. In order to mitigate the concerns for potential systemic side effects, we pursued liver-targeted HIF-PHD inhibitors relying on uptake via organic anion transporting polypeptides (OATPs). Starting from a systemic HIF-PHD inhibitor (1), medicinal chemistry efforts directed toward reducing permeability and, at the same time, maintaining oral absorption led to the synthesis of an array of structurally diverse hydroxypyridone analogues. Compound 28a was chosen for further profiling, because of its excellent in vitro profile and liver selectivity. This compound significantly increased hemoglobin levels in rats, following chronic QD oral administration, and displayed selectivity over systemic effects.
RESUMEN
8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Descubrimiento de Drogas , Imidazoles/farmacología , Morfolinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Artritis Reumatoide/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/síntesis química , Imidazoles/química , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Modelos Moleculares , Estructura Molecular , Morfolinas/síntesis química , Morfolinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas/metabolismo , Relación Estructura-Actividad , Regulador Transcripcional ERG/antagonistas & inhibidores , Regulador Transcripcional ERG/metabolismoRESUMEN
We report the design and synthesis of a series of novel Bruton's Tyrosine Kinase (BTK) inhibitors with a carboxylic acid moiety in the ribose pocket. This series of compounds has demonstrated much improved off-target selectivities including adenosine uptake (AdU) inhibition compared to the piperidine amide series. Optimization of the initial lead compound 4 based on BTK enzyme inhibition, and human peripheral blood mononuclear cell (hPBMC) and human whole blood (hWB) activity led to the discovery of compound 40, with potent BTK inhibition, reduced off target activities, as well as favorable pharmacokinetic profile in both rat and dog.
Asunto(s)
Ácidos Carboxílicos/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa , Animales , Humanos , RatasRESUMEN
The inhibition of aldosterone synthase (CYP11B2) may be an effective treatment of hypertension and heart failure, among other ailments. Previously reported benzimidazole CYP11B2 inhibitors led the way for bioisosteric imidazopyridines that are both potent and selective over CYP11B1.
Asunto(s)
Citocromo P-450 CYP11B2/antagonistas & inhibidores , Imidazoles/farmacología , Piridinas/farmacología , Animales , Cricetulus , Humanos , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/farmacocinética , Macaca mulatta , Masculino , Microsomas Hepáticos/metabolismo , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacocinética , Ratas Wistar , Esteroide 11-beta-Hidroxilasa/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
RESUMEN
The synthesis and preliminary structure-activity relationships (SAR) of a novel class of vasopressin V(1B) receptor antagonists are described. Hit compound 5, identified via high throughput screening of the corporate collection, showed good activity in a V(1B) binding assay (K(i) 63 nM) but did not possess the lead-like physicochemical properties typically required in a hit compound. A 'deletion approach' on the HTS hit 5 was performed, with the focus on improvement of physicochemical properties, yielding the selective V(1B) antagonist 9f (K(i) 190 nM), with improved druglike characteristics.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Estructura Molecular , Unión Proteica/efectos de los fármacos , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
The purpose of the study was to examine the potential of inhibition of cathepsin S as a treatment for autoimmune diseases. A highly selective cathepsin S inhibitor, CSI-75, was shown to upregulate levels of the cathepsin S substrate, invariant chain Lip10, in vitro as well as in vivo in C57Bl/6 mice after oral administration. Functional activity of the compound was shown by a reduction in the OVA-specific response of OVA-sensitized splenocytes from C57Bl/6 mice as well as from OVA-TCR transgenic mice (DO11.10). Since these studies revealed a selective suppression of the Th1 and Th17 cytokines causing a shift to Th2, CSI-75 was tested in the murine HC-gp39-immunization model. Indeed, CSI-75 specifically reduced the circulating HC-gp39-specific IgG2a in these mice indicating selective inhibition of the Th1 type of response in vivo. The importance of especially the Th1 and Th17 cell subsets in the pathology of autoimmune diseases, renders CatS inhibition a highly interesting potential therapeutic treatment of autoimmune diseases. Therefore, CSI-75 was tested in a murine model of multiple sclerosis (i.e. experimental autoimmune encephalomyelitis (EAE)) in a semi-therapeutic setting (ie. oral treatment after initial sensitization to antigen). Finally, in a murine model with features resembling rheumatoid arthritis (the collagen-induced arthritis (CIA) model), CSI-75 was tested in a therapeutic manner (after disease development). CSI-75 caused a significant reduction in disease score in both disease models, indicating a promising role for CatS inhibitors in the area of therapeutic treatments for autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Catepsinas/antagonistas & inhibidores , Piperidinas/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Piridinas/uso terapéutico , Administración Oral , Animales , Células Presentadoras de Antígenos/efectos de los fármacos , Artritis Experimental/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Piperidinas/administración & dosificación , Inhibidores de Proteasas/administración & dosificación , Piridinas/administración & dosificación , Células TH1/fisiologíaRESUMEN
Based on the theoretical understanding of the in vivo lysosomotropism, by adjusting the pk(a) of basic nitrogen containing cathepsin S inhibitors, a set of compounds with pk(a) 6-8 were identified to have excellent cell based Lip10 activity, yet avoiding undesired sequestration in spleen.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Nitrógeno/química , Inhibidores de Proteasas/química , Piridinas/química , Animales , Catepsinas/metabolismo , Ratones , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position.
Asunto(s)
Compuestos de Anilina/síntesis química , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Amidas/síntesis química , Amidas/farmacología , Compuestos de Anilina/farmacología , Animales , Inhibidores de Cisteína Proteinasa/farmacología , Flúor , Humanos , Cetonas , Relación Estructura-ActividadRESUMEN
Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (>1000-fold), displayed a highly attractive overall profile.
Asunto(s)
Catepsina K/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Nitrilos/síntesis química , Nitrilos/farmacología , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Diseño de Fármacos , Descubrimiento de Drogas , Indicadores y Reactivos , Modelos Moleculares , Curva ROC , Relación Estructura-Actividad , Torsades de Pointes/tratamiento farmacológicoRESUMEN
6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile analogues were identified as potent and selective cathepsin S inhibitor against both purified enzyme and in human JY cell based cellular assays. This core has a very stable thio-trapping nitrile war-head in comparison with the well reported pyrimidine-2-carbonitrile cysteine cathepsin inhibitors. Compound 47 is also very potent in in vivo mouse spleenic Lip10 accumulation assays.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Nitrilos/química , Inhibidores de Proteasas/química , Piridinas/química , Animales , Sitios de Unión , Catepsinas/metabolismo , Línea Celular , Cristalografía por Rayos X , Humanos , Ratones , Nitrilos/síntesis química , Nitrilos/farmacocinética , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Relación Estructura-ActividadRESUMEN
Starting from previously disclosed equally potent cathepsin K and S inhibitor 4-propyl-6-(3-trifluoromethylphenyl)pyrimidine-2-carbonitrile 1, a novel 2-phenyl-9H-purine-6-carbonitrile scaffold was identified to provide potent and selective cathepsin S inhibitors.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Nitrilos/química , Inhibidores de Proteasas/química , Purinas/química , Dominio Catalítico , Catepsina K/antagonistas & inhibidores , Catepsina K/metabolismo , Catepsinas/metabolismo , Línea Celular , Simulación por Computador , Humanos , Nitrilos/síntesis química , Nitrilos/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Purinas/síntesis química , Purinas/farmacología , Pirimidinas/químicaRESUMEN
Using computer aided modelling studies, a new extended P2/S2 interaction was identified. This extended region can accommodate a variety of functional groups, such as aryls and basic amines. It was discovered that the N3 nitrogen of the pyrimidine-2-carbonitrile is critical for its cathepsin cysteine protease inhibition. N1 nitrogen also contributes to the inhibitory activity, but to a very limited degree. An 'in situ double activation' mechanism was proposed to explain these results.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Nitrilos/química , Inhibidores de Proteasas/química , Pirimidinas/química , Sitios de Unión , Catepsinas/metabolismo , Simulación por Computador , Humanos , Modelos Moleculares , Nitrilos/síntesis química , Nitrilos/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacologíaRESUMEN
Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with good pharmacokinetic profiles, for example, compound 20 showed high catK potency (IC(50)=4nM), >580-fold selectivity over catL and catB, and oral bioavailability in the rat of 52%.
Asunto(s)
Catepsina K/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/química , Pirimidinas/química , Administración Oral , Animales , Sitios de Unión , Catepsina K/metabolismo , Línea Celular , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacocinética , Diseño de Fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A novel dioxo-triazine series of cathepsin K inhibitors was identified from HTS. A rapid exploratory programme led to the discovery of potent and selective cathepsin K inhibitors, typified by compound 24 which displayed IC(50) values of 17nM against catK and >10,000nM in catL, catB and catS assays.
Asunto(s)
Catepsina K/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/química , Triazinas/química , Sitios de Unión , Dominio Catalítico , Catepsina K/metabolismo , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacología , Ensayos Analíticos de Alto Rendimiento , Humanos , Relación Estructura-Actividad , Triazinas/síntesis química , Triazinas/farmacología , Uracilo/análogos & derivados , Uracilo/síntesis química , Uracilo/química , Uracilo/farmacologíaRESUMEN
The synthesis of three potent new antitumor agents is described: the A83586C-citropeptin hybrid (1), the A83586C-GE3 hybrid (2), and l-Pro-A83586C (3). Significantly, compounds 1 and 2 function as highly potent inhibitors of beta-catenin/TCF4 signaling within cancer cells, while simultaneously downregulating osteopontin (Opn) expression. A83586C antitumor cyclodepsipeptides also inhibit E2F-mediated transcription by downregulating E2F1 expression and inducing dephosphorylation of the oncogenic hyperphosphorylated retinoblastoma protein (pRb).
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteínas de Unión al ADN/antagonistas & inhibidores , Depsipéptidos/síntesis química , Depsipéptidos/farmacología , Factores de Transcripción E2F/metabolismo , Factores de Transcripción/antagonistas & inhibidores , beta Catenina/antagonistas & inhibidores , Antineoplásicos/química , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Depsipéptidos/química , Ensayos de Selección de Medicamentos Antitumorales , Factor de Transcripción E2F1/metabolismo , Humanos , Concentración 50 Inhibidora , Factor de Transcripción 4RESUMEN
The orexin system plays a key role in the control of eating, sleeping and rewarding. This review summarizes the latest developments in the identification of orexin receptor antagonists. By using a selective orexin-1 receptor antagonist, SB-334867-A (GlaxoSnzithKline plc), the in vivo futctions of both the orexin-1 and orexin-2 receptors have been elucidated. This review also sunmmarizes the literature and current opinions up to May 2006 on the therapeutic utility of orexin receptor antagonists for the treatment of eating disorders, sleeping disorders and drug addiction.