RESUMEN
RATIONALE: αv integrins, key regulators of transforming growth factor-ß activation and fibrogenesis in in vivo models of pulmonary fibrosis, are expressed on abnormal epithelial cells (αvß6) and fibroblasts (αvß1) in fibrotic lungs. OBJECTIVES: We evaluated multiple αv integrin inhibition strategies to assess which most effectively reduced fibrogenesis in explanted lung tissue from patients with idiopathic pulmonary fibrosis. METHODS: Selective αvß6 and αvß1, dual αvß6/αvß1, and multi-αv integrin inhibitors were characterized for potency, selectivity, and functional activity by ligand binding, cell adhesion, and transforming growth factor-ß cell activation assays. Precision-cut lung slices generated from lung explants from patients with idiopathic pulmonary fibrosis or bleomycin-challenged mouse lungs were treated with integrin inhibitors or standard-of-care drugs (nintedanib or pirfenidone) and analyzed for changes in fibrotic gene expression or TGF-ß signaling. Bleomycin-challenged mice treated with dual αvß6/αvß1 integrin inhibitor, PLN-74809, were assessed for changes in pulmonary collagen deposition and Smad3 phosphorylation. MEASUREMENTS AND MAIN RESULTS: Inhibition of integrins αvß6 and αvß1 was additive in reducing type I collagen gene expression in explanted lung tissue slices from patients with idiopathic pulmonary fibrosis. These data were replicated in fibrotic mouse lung tissue, with no added benefit observed from inhibition of additional αv integrins. Antifibrotic efficacy of dual αvß6/αvß1 integrin inhibitor PLN-74809 was confirmed in vivo, where dose-dependent inhibition of pulmonary Smad3 phosphorylation and collagen deposition was observed. PLN-74809 also, more potently, reduced collagen gene expression in fibrotic human and mouse lung slices than clinically relevant concentrations of nintedanib or pirfenidone. CONCLUSIONS: In the fibrotic lung, dual inhibition of integrins αvß6 and αvß1 offers the optimal approach for blocking fibrogenesis resulting from integrin-mediated activation of transforming growth factor-ß.
Asunto(s)
Antifibróticos/farmacología , Células Epiteliales/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Integrina alfa6beta1/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Receptores de Vitronectina/antagonistas & inhibidores , Animales , Bleomicina , Línea Celular , Técnicas de Cocultivo , Cadena alfa 1 del Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I/metabolismo , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Células Epiteliales/patología , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Integrina alfa6beta1/metabolismo , Pulmón/metabolismo , Pulmón/patología , Ratones Endogámicos C57BL , Fosforilación , Receptores de Vitronectina/metabolismo , Transducción de Señal , Proteína smad3/metabolismoRESUMEN
A potent, in vivo efficacious 11ß hydroxysteroid dehydrogenase type 1 (11ß HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11ß HSD1 activity in human adipocytes with an IC50 of 4.3nM and in primary human adipose tissue with an IC80 of 53nM. Oral administration of 11j to cynomolgus monkey inhibited 11ß HSD1 activity in adipose tissue. Compound 11j exhibited >1000× selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Oxazinas/química , Piridonas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Administración Oral , Animales , Sitios de Unión , Células Cultivadas , Sistema Enzimático del Citocromo P-450/metabolismo , Evaluación Preclínica de Medicamentos , Semivida , Concentración 50 Inhibidora , Macaca fascicularis , Simulación del Acoplamiento Molecular , Oxazinas/administración & dosificación , Oxazinas/farmacocinética , Estructura Terciaria de Proteína , Piridonas/administración & dosificación , Piridonas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Liver X receptor (LXR) agonists have been reported to lower brain amyloid beta (Aß) and thus to have potential for the treatment of Alzheimer's disease. Structure and property based design led to the discovery of a series of orally bioavailable, brain penetrant LXR agonists. Oral administration of compound 18 to rats resulted in significant upregulation of the expression of the LXR target gene ABCA1 in brain tissue, but no significant effect on Aß levels was detected.
Asunto(s)
Encéfalo/metabolismo , Receptores X del Hígado/efectos de los fármacos , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Animales , Masculino , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Regulación hacia ArribaRESUMEN
Mineralocorticoid receptor (MR) antagonists continue to be a prevalent area of research in the pharmaceutical industry. Herein we report the discovery of various spirooxindole and dibenzoxazepine constructs as potent MR antagonists. SAR analysis of our spirooxindole hit led to highly potent compounds containing polar solubilizing groups, which interact with the helix-11 region of the MR ligand binding domain (LBD). Various dibenzoxazepine moieties were also prepared in an effort to replace a known dibenzoxepane system which interacts with the hydrophobic region of the MR LBD. In addition, an X-ray crystal structure was obtained from a highly potent compound which was shown to exhibit both partial agonist and antagonist modes of action against MR.
Asunto(s)
Dibenzoxazepinas/farmacología , Indoles/farmacología , Antagonistas de Receptores de Mineralocorticoides/farmacología , Receptores de Mineralocorticoides/metabolismo , Compuestos de Espiro/farmacología , Cristalografía por Rayos X , Dibenzoxazepinas/síntesis química , Dibenzoxazepinas/química , Relación Dosis-Respuesta a Droga , Humanos , Indoles/síntesis química , Indoles/química , Antagonistas de Receptores de Mineralocorticoides/síntesis química , Antagonistas de Receptores de Mineralocorticoides/química , Modelos Moleculares , Estructura Molecular , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
Investigation of various heterocyclic core isosteres of imidazopyrazines 1 & 2 yielded purine derivatives 3 & 8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of 20 as a leading compound. Compound 20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Purinas/química , Purinas/farmacología , Agammaglobulinemia Tirosina Quinasa , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/enzimología , Linfocitos B/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Ratones , Modelos Moleculares , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Proteínas Tirosina Quinasas/metabolismo , RatasRESUMEN
As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.
Asunto(s)
Química Farmacéutica , Poder Psicológico , Humanos , FemeninoRESUMEN
As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.
RESUMEN
A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38α inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and α-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2mpk (equivalent to 10mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10mpk of 1 itself. At a suspension dose of 142mpk (equivalent to 100mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of 1. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates.
Asunto(s)
Dacarbazina/análogos & derivados , Profármacos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/farmacología , Triazinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Dacarbazina/química , Relación Dosis-Respuesta a Droga , Concentración de Iones de Hidrógeno , Modelos Moleculares , Estructura Molecular , Profármacos/administración & dosificación , Profármacos/síntesis química , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/síntesis química , Pirroles/administración & dosificación , Pirroles/síntesis química , Ratas , Solubilidad , Relación Estructura-Actividad , Temperatura , Triazinas/administración & dosificación , Triazinas/síntesis química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38ß isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.
Asunto(s)
Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Sitios de Unión , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Simulación de Dinámica Molecular , Unión Proteica , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
On the occasion of the 2023 International Women's Day on March 8, 2023, we want to celebrate and highlight the contributions of many women volunteers in the American Chemical Society Division of Medicinal Chemistry (ACS MEDI).
Asunto(s)
Química Farmacéutica , Humanos , Femenino , Estados UnidosRESUMEN
On the occasion of the 2023 International Women's Day on March 8, 2023, we want to celebrate and highlight the contributions of many women volunteers in the American Chemical Society Division of Medicinal Chemistry (ACS MEDI).
RESUMEN
Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation.
Asunto(s)
Antiinflamatorios/química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirroles/química , Triazinas/química , Administración Oral , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Artritis/tratamiento farmacológico , Sitios de Unión , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Ratones , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Estructura Terciaria de Proteína , Ratas , Relación Estructura-Actividad , Triazinas/farmacología , Triazinas/uso terapéuticoRESUMEN
TTK is an essential spindle assembly checkpoint enzyme in many organisms. It plays a central role in tumor cell proliferation and is aberrantly overexpressed in a wide range of tumor types. We recently reported on a series of potent and selective TTK inhibitors with strong antiproliferative activity in triple negative breast cancer (TNBC) cell lines (8: TTK IC50 = 3.0 nM; CAL-51 IC50 = 84.0 nM). Inspired by previously described potent tricyclic TTK inhibitor 6 (TTK IC50 = 0.9 nM), we embarked on a structure-enabled design and optimization campaign to identify an improved series with excellent potency, TTK selectivity, solubility, CYP inhibition profile, and in vivo efficacy in a TNBC xenograft model. These efforts culminated in the discovery of 25 (TTK IC50 = 3.0 nM; CAL-51 IC50 = 16.0 nM), which showed significant single-agent efficacy when dosed iv in a TNBC xenograft model without body weight loss.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Antineoplásicos , Neoplasias de la Mama , Línea Celular Tumoral , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead (3) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 (57) was selected for clinical development.
Asunto(s)
Ciclohexanoles/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Proteína Quinasa C-theta/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Animales , Células CACO-2 , Proliferación Celular/efectos de los fármacos , Ciclohexanoles/síntesis química , Ciclohexanoles/metabolismo , Humanos , Factores Inmunológicos/síntesis química , Factores Inmunológicos/metabolismo , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Proteína Quinasa C-delta/antagonistas & inhibidores , Proteína Quinasa C-delta/metabolismo , Proteína Quinasa C-theta/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Pirimidinas/síntesis química , Pirimidinas/metabolismo , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacosRESUMEN
The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38 α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.
Asunto(s)
Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Nitrógeno/química , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/química , Azufre/química , Tiazoles/química , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacologíaRESUMEN
The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed.
Asunto(s)
Proteína Quinasa 14 Activada por Mitógenos/química , Inhibidores de Proteínas Quinasas/síntesis química , Pirazoles/farmacología , Animales , Cristalografía por Rayos X , Ratones , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Unión Proteica , Conformación Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC(50) of 15.2 nM against human 11ß-HSD1 in adipocytes. Optimization for increased adipocyte potency, metabolic stability and selectivity afforded 11k and 11l, both of which were >25% orally bioavailable in rat.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/farmacología , Inhibidores Enzimáticos/farmacología , Adamantano/química , Animales , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Modelos Moleculares , RatasRESUMEN
Integrins comprise a family of 24 heterodimeric transmembrane receptors that mediate cell attachment to the extracellular matrix and are critical for cell signaling. There are four classes of integrins: collagen-binding, Arg-Gly-Asp (RGD)-binding, laminin-binding, and leukocyte integrins. Owing to their involvement in modulating various critical cellular processes including proliferation, migration, differentiation, and survival, integrins have been investigated as therapeutic targets. Important progress has been made in the structural elucidation of integrins in recent years. Here we examine the protein-ligand interactions of integrin complexes and the related structure-based drug design of integrin inhibitors. Published integrin structures in the Protein Data Bank (PDB) are examined to gain insights into integrin-ligand interactions as well as the conformational dynamics of integrins.
Asunto(s)
Integrinas/metabolismo , Ligandos , Sitios de Unión , Bases de Datos de Proteínas , Diseño de Fármacos , Humanos , Integrinas/antagonistas & inhibidores , Leucocitos/metabolismo , Simulación del Acoplamiento Molecular , Oligopéptidos/química , Oligopéptidos/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Subunidades de Proteína/antagonistas & inhibidores , Subunidades de Proteína/metabolismoRESUMEN
Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antineoplásicos/farmacología , Mieloma Múltiple/tratamiento farmacológico , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Concentración 50 Inhibidora , Ratones , Mieloma Múltiple/patología , Recurrencia , Estereoisomerismo , Insuficiencia del Tratamiento , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Triple negative breast cancer (TNBC) is an aggressive disease with high relapse rates and few treatment options. Outlined in previous publications, we identified a series of potent, dual TTK/CLK2 inhibitors with strong efficacy in TNBC xenograft models. Pharmacokinetic properties and kinome selectivity were optimized, resulting in the identification of a new series of potent, selective, and orally bioavailable TTK inhibitors. We describe here the structure-activity relationship of the 2,4-disubstituted-7 H-pyrrolo[2,3- d]pyrimidine series, leading to significant single agent efficacy in a TNBC xenograft model without body weight loss. The design effort evolving an iv-dosed TTK/CLK2 inhibitor to an orally bioavailable TTK inhibitor is described.