RESUMEN
The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.
Asunto(s)
Hipoglucemiantes/síntesis química , PPAR alfa/agonistas , PPAR gamma/agonistas , Pirrolidinas/química , Animales , Glucemia/análisis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Femenino , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Ligandos , Ratones , Ratones Obesos , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/uso terapéutico , Estereoisomerismo , Relación Estructura-Actividad , Triglicéridos/sangreRESUMEN
Acylureas and acyclic imides are found to be excellent isosteres for 2-acylamino-1,3,4-thiadiazole in the azaxanthene-based series of glucocorticoid receptor (GR) agonists. The results reported herein show that primary acylureas maintain high affinity and selectivity for GR while providing improved CYP450 inhibition and pharmacokinetic profile over 2-acylamino-1,3,4-thiadiazoles. General methods for synthesis of a variety of acylureas and acyclic imides from a carboxylic acid were utilized and are described.
Asunto(s)
Descubrimiento de Drogas , Compuestos Heterocíclicos con 3 Anillos/farmacología , Receptores de Glucocorticoides/agonistas , Tiadiazoles/farmacología , Urea/farmacología , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/química , Humanos , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Tiadiazoles/química , Urea/análogos & derivados , Urea/químicaRESUMEN
SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors.
Asunto(s)
Indazoles/síntesis química , Indazoles/farmacología , Receptores de Glucocorticoides/agonistas , Amidas/química , Amidas/farmacología , Humanos , Indazoles/química , Modelos Moleculares , Unión Proteica/efectos de los fármacos , Receptores de Glucocorticoides/química , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Urea/química , Urea/farmacologíaRESUMEN
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
Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure.
Asunto(s)
Amidas/química , Amidas/farmacología , Descubrimiento de Drogas , Receptores de Glucocorticoides/agonistas , Sitios de Unión , Cristalografía por Rayos X , Humanos , Indazoles/química , Indazoles/farmacología , Estructura Molecular , Unión Proteica/efectos de los fármacos , Esteroides/química , Esteroides/farmacología , Relación Estructura-ActividadRESUMEN
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
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
A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising dissociation profile in discriminating between transrepression and transactivation activities. 17a is a partial agonist of GR-mediated transactivation which elicits potent and efficacious transrepression in reporter gene assays. A hypothetical binding mode is provided which accounts for the induction of functional activity by a bridgehead methyl group.
Asunto(s)
Antracenos/farmacología , Descubrimiento de Drogas , Receptores de Glucocorticoides/metabolismo , Antracenos/química , Línea Celular , Cristalografía por Rayos X , Descubrimiento de Drogas/métodos , Glucocorticoides/química , Glucocorticoides/farmacología , Humanos , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/fisiología , Relación Estructura-ActividadRESUMEN
The design, synthesis and structure-activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPARalpha/gamma agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic db/db mice.
Asunto(s)
Azoles/síntesis química , Diseño de Fármacos , PPAR alfa/agonistas , PPAR gamma/agonistas , Animales , Azoles/farmacología , Línea Celular/enzimología , Cristalografía por Rayos X , Femenino , Humanos , Concentración de Iones de Hidrógeno , Ratones , Ratones Transgénicos , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Relación Estructura-ActividadRESUMEN
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
A novel class of azetidinone acid-derived dual PPARalpha/gamma agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARalpha and PPARgamma receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.
Asunto(s)
Azetidinas/química , Azetidinas/farmacología , PPAR alfa/agonistas , PPAR gamma/agonistas , Administración Oral , Animales , Azetidinas/síntesis química , Disponibilidad Biológica , Cobre/farmacología , Cristalografía por Rayos X , Inhibidores Enzimáticos del Citocromo P-450 , Diabetes Mellitus Experimental/tratamiento farmacológico , Dislipidemias/tratamiento farmacológico , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Glucosa/metabolismo , Ratones , Ratones Mutantes , Estructura Molecular , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Conformación Proteica , Estereoisomerismo , Relación Estructura-Actividad , Triglicéridos/sangreRESUMEN
Rational design, synthesis, and SAR studies of a novel class of benzothiazole based inhibitors of p38alpha MAP kinase are described. The issue of metabolic instability associated with vicinal phenyl, benzo[d]thiazol-6-yl oxazoles/imidazoles was addressed by the replacement of the central oxazole or imidazole ring with an aminopyrazole system. The proposed binding mode of this new class of p38alpha inhibitors was confirmed by X-ray crystallographic studies of a representative inhibitor (6a) bound to the p38alpha enzyme.
Asunto(s)
Benzotiazoles/química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Animales , Células Cultivadas/efectos de los fármacos , Células Cultivadas/enzimología , Cristalografía por Rayos X , Humanos , Lipopolisacáridos/farmacología , Ratones , Microsomas/efectos de los fármacos , Microsomas/enzimología , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The synthesis and structure-activity relationships (SAR) of p38 alpha MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38 alpha MAP kinase with excellent cellular potency toward the inhibition of TNFalpha production. Compound 2x was highly efficacious in vivo in inhibiting TNFalpha production in an acute murine model of TNFalpha production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38 alpha is also disclosed.
Asunto(s)
Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/químicaRESUMEN
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 p38alpha MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a potent and selective p38alpha inhibitor that is orally efficacious in rodent models of acute and chronic inflammation.
Asunto(s)
Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Tiazoles/farmacología , Animales , Artritis/tratamiento farmacológico , Células CACO-2 , Permeabilidad de la Membrana Celular/efectos de los fármacos , Células Cultivadas , Cristalografía por Rayos X , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Lipopolisacáridos/farmacología , Masculino , Ratones , Microsomas Hepáticos/efectos de los fármacos , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Estructura Molecular , Monocitos/citología , Monocitos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Ratas Endogámicas Lew , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacocinética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The concept of quantitative SAR (QSAR) is inherently imbued with an expectation of predictivity, novel insights and the generation of useful hypotheses, particularly as applied to the drug discovery process. However, even recently developed QSAR models often appear to be flawed, characterized by mediocre predictive power and undecipherable descriptors. As a result, users may be able to derive only a vague notion of which molecular features are correlated to activity. Consideration of several precautions is necessary to attempt to circumvent the misuse and misunderstanding of the QSAR technique. Issues related with QSAR include an erroneous association of correlation with causation, the close relationship between large numbers of descriptors and the effect of chance factor, the misuse of the 'leave-one-out' paradigm, and finally, the QSAR enigma, wherein the predictivity of a model is not necessarily a measure of a model's utility.
Asunto(s)
Diseño de Fármacos , Farmacología Clínica/tendencias , Relación Estructura-Actividad Cuantitativa , Biología Computacional , Preparaciones Farmacéuticas/química , Investigación , DescriptoresRESUMEN
2-aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 approximately 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFalpha production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Pirimidinas/síntesis química , Tiazoles/síntesis química , Familia-src Quinasas/antagonistas & inhibidores , Administración Oral , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Enfermedad Crónica , Dasatinib , Femenino , Humanos , Técnicas In Vitro , Inflamación/sangre , Inflamación/inducido químicamente , Interleucina-2/antagonistas & inhibidores , Lipopolisacáridos , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Modelos Moleculares , Unión Proteica , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Ratas Endogámicas Lew , Relación Estructura-Actividad , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Tiazoles/química , Tiazoles/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation.
RESUMEN
Small molecule inhibition of protein kinases in the treatment of significant diseases such as cancer, Alzheimer's disease, diabetes, and rheumatoid arthritis has attracted significant attention over the past two decades and has clearly become one of the most significant challenges for drug discovery in the 21st century. While the recent identification of 518 different kinases in the human genome has offered a wealth of opportunities for drug intervention in the treatment of these diseases, it has also created a daunting challenge with respect to selective kinase inhibition as a viable strategy in target-based drug design. Over the past decade, the design and development of a small molecule that selectively inhibits the p38 mitogen activated protein (MAP) kinase has clearly emerged as one of these challenges within the industry. This review will focus on the comparison of the x-ray crystal structures and binding models of the most recent p38 inhibitor-enzyme complexes and the identification of the structural elements and interactions that may be important in providing inhibitor potency and selectivity toward the p38 MAP kinase.