RESUMEN
As a member of the Janus (JAK) family of nonreceptor tyrosine kinases, TYK2 plays an important role in mediating the signaling of pro-inflammatory cytokines including IL-12, IL-23, and type 1 interferons. The nicotinamide 4, identified by a SPA-based high-throughput screen targeting the TYK2 pseudokinase domain, potently inhibits IL-23 and IFNα signaling in cellular assays. The described work details the optimization of this poorly selective hit (4) to potent and selective molecules such as 47 and 48. The discoveries described herein were critical to the eventual identification of the clinical TYK2 JH2 inhibitor (see following report in this issue). Compound 48 provided robust inhibition in a mouse IL-12-induced IFNγ pharmacodynamic model as well as efficacy in an IL-23 and IL-12-dependent mouse colitis model. These results demonstrate the ability of TYK2 JH2 domain binders to provide a highly selective alternative to conventional TYK2 orthosteric inhibitors.
Asunto(s)
Niacinamida/análogos & derivados , Ácidos Nicotínicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , TYK2 Quinasa/antagonistas & inhibidores , Regulación Alostérica , Animales , Humanos , Ligandos , Ratones , Niacinamida/metabolismo , Niacinamida/farmacología , Ácidos Nicotínicos/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Descubrimiento de Drogas , Compuestos Heterocíclicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , TYK2 Quinasa/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Animales , Cristalografía por Rayos X , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacocinética , Compuestos Heterocíclicos/uso terapéutico , Humanos , Ratones , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Sitios de Unión , Dominio Catalítico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Janus Quinasa 3/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.
Asunto(s)
Diseño de Fármacos , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Niacinamida/química , Inhibidores de Proteínas Quinasas/química , Sitios de Unión , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Janus Quinasa 3/química , Janus Quinasa 3/metabolismo , Conformación Molecular , Simulación de Dinámica Molecular , Niacinamida/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug 2 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug 1 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of 1 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, 2 demonstrated similar efficacy to 1. Most importantly, it was shown in clinical studies that prodrug 2 was indeed effective in addressing the pH-dependent absorption issue associated with 1.
Asunto(s)
Organofosfatos/farmacología , Fenilacetatos/farmacología , Profármacos/química , Profármacos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Artritis Experimental/tratamiento farmacológico , Disponibilidad Biológica , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Macaca fascicularis , Masculino , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Estructura Molecular , Organofosfatos/química , Fenilacetatos/química , Profármacos/farmacocinética , Inhibidores de Proteínas Quinasas/química , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-ActividadRESUMEN
A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.
Asunto(s)
Descubrimiento de Drogas , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Piridazinas/química , Pirroles/química , Administración Oral , Animales , Ensayo de Inmunoadsorción Enzimática , Humanos , Interferón gamma/metabolismo , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Conformación Proteica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Relación Estructura-Actividad , Distribución TisularRESUMEN
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
The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp(2) character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Pirroles/síntesis química , Triazinas/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Disponibilidad Biológica , Células CACO-2 , Cristalografía por Rayos X , Femenino , Humanos , Enlace de Hidrógeno , Técnicas In Vitro , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Proteína Quinasa 14 Activada por Mitógenos/química , Modelos Moleculares , Conformación Molecular , Unión Proteica , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Triazinas/farmacocinética , Triazinas/farmacología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
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
A novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38 alpha MAP kinase inhibitors. The synthesis, structure-activity relationships (SAR), and in vivo activity of selected analogs from this class of inhibitors are reported. Additional studies based on X-ray co-crystallography have revealed that one of the potent inhibitors from this series binds to the DFG-out conformation of the p38 alpha enzyme.
Asunto(s)
Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/química , Triazinas/síntesis química , Triazinas/farmacología , Amidas/química , Animales , Cristalografía por Rayos X , Femenino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Triazinas/química , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
A novel structural class of p38 mitogen-activated protein (MAP) kinase inhibitors consisting of substituted 4-(phenylamino)-pyrrolo[2,1- f][1,2,4]triazines has been discovered. An initial subdeck screen revealed that the oxindole-pyrrolo[2,1- f][1,2,4]triazine lead 2a displayed potent enzyme inhibition (IC 50 60 nM) and was active in a cell-based TNFalpha biosynthesis inhibition assay (IC 50 210 nM). Replacement of the C4 oxindole with 2-methyl-5- N-methoxybenzamide aniline 9 gave a compound with superior p38 kinase inhibition (IC 50 10 nM) and moderately improved functional inhibition in THP-1 cells. Further replacement of the C6 ester of the pyrrolo[2,1- f][1,2,4]triazine with amides afforded compounds with increased potency, excellent oral bioavailability, and robust efficacy in a murine model of acute inflammation (murine LPS-TNFalpha). In rodent disease models of chronic inflammation, multiple compounds demonstrated significant inhibition of disease progression leading to the advancement of 2 compounds 11b and 11j into further preclinical and toxicological studies.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Pirroles/síntesis química , Triazinas/síntesis química , Administración Oral , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Femenino , Humanos , Técnicas In Vitro , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Proteína Quinasa 14 Activada por Mitógenos/química , Modelos Moleculares , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Ratas Endogámicas Lew , Relación Estructura-Actividad , Triazinas/farmacocinética , Triazinas/farmacología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/sangreRESUMEN
The synthesis and structure-activity relationships (SAR) of p38alpha MAP kinase inhibitors based on heterobicyclic scaffolds are described. This effort led to the identification of compound (21) as a potent inhibitor of p38alpha MAP kinase with good cellular potency toward the inhibition of TNF-alpha production. X-ray co-crystallography of an oxalamide analog (24) bound to unphosphorylated p38alpha is also disclosed.
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/farmacología , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Compuestos Bicíclicos con Puentes/química , Cristalografía por Rayos X , Compuestos Heterocíclicos/química , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
As part of our efforts to identify potent HIV-1 protease inhibitors that are active against resistant viral strains, structural modification of the azacyclic urea (I) was undertaken by incorporating acyl groups as P(1)' ligands. The extensive SAR study has yielded a series of N-acyl azacyclic ureas (II), which are highly potent against both wild-type and multiple PI-resistant viral strains.
Asunto(s)
Inhibidores de la Proteasa del VIH/síntesis química , VIH-1/efectos de los fármacos , Compuestos Aza/síntesis química , Compuestos Aza/farmacología , Diseño de Fármacos , Resistencia a Múltiples Medicamentos , Inhibidores de la Proteasa del VIH/uso terapéutico , Ligandos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Ritonavir/síntesis química , Ritonavir/uso terapéutico , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/síntesis química , Urea/farmacologíaRESUMEN
A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activity has been discovered. The initial hit (compound 1a) was identified through screening the Pharmacopeia ECLiPS compound collection. SAR modification led to the identification of a short acting triaminotriazine aniline methoxyamide (compound 1m) possessing in vitro and in vivo oral activity in animal models of acute and chronic inflammatory disease. An X-ray crystal structure of compound 1m in this class, cocrystallized with unactivated p38 alpha protein, indicates that these compounds bind to the ATP binding pocket and possess key H-bonding interactions within a deeper cleft. Hydrogen bonding between one of the triazine nitrogens and the backbone NH of the Met109 residue occurs through a water molecule. The methoxyamide NH and carbonyl oxygen are within H-bonding distance of Glu71 and Asp168.
Asunto(s)
Amidas/síntesis química , Compuestos de Anilina/síntesis química , Antiinflamatorios no Esteroideos/síntesis química , Benzamidas/síntesis química , Triazinas/síntesis química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Administración Oral , Amidas/química , Amidas/farmacología , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Benzamidas/química , Benzamidas/farmacología , Cristalografía por Rayos X , Femenino , Humanos , Técnicas In Vitro , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Ratas , Ratas Endogámicas Lew , Relación Estructura-Actividad , Triazinas/química , Triazinas/farmacología , Factor de Necrosis Tumoral alfa/biosíntesis , Proteínas Quinasas p38 Activadas por Mitógenos/químicaRESUMEN
A series of unique indazoles and pyridoindolones have been rationally designed and synthesized as novel classes of cannabinoid ligands based on a proposed bioactive amide conformation. This has led to the discovery of the novel indolopyridone 3a as a conformationally constrained cannabinoid ligand that displays high affinity for the CB2 receptor (K(i)(CB2) = 1.0 nM) and possesses antiinflammatory properties when administered orally in an in vivo murine inflammation model.