RESUMEN
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) has been found to catalyze the amidation of acyl imidazoles. The rate acceleration is especially evident with traditionally unreactive, electron-deficient anilines. DBU is readily available and offers safety and cost advantages over more commonly employed catalysts such as 1-hydroxybenzotriazole.
Asunto(s)
Amidas/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Imidazoles/química , Amidas/química , Catálisis , Estructura MolecularRESUMEN
There is a critical need for safer and more convenient treatments for organ transplant rejection and autoimmune disorders such as rheumatoid arthritis. Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are involved in the signaling of multiple cytokines important for various T cell functions. Blockade of the JAK1/JAK3-STAT pathway with a small molecule was anticipated to provide therapeutic immunosuppression/immunomodulation. The Pfizer compound library was screened against the catalytic domain of JAK3 resulting in the identification of a pyrrolopyrimidine-based series of inhibitors represented by CP-352,664 (2a). Synthetic analogues of 2a were screened against the JAK enzymes and evaluated in an IL-2 induced T cell blast proliferation assay. Select compounds were evaluated in rodent efficacy models of allograft rejection and destructive inflammatory arthritis. Optimization within this chemical series led to identification of CP-690,550 1, a potential first-in-class JAK inhibitor for treatment of autoimmune diseases and organ transplant rejection.
Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Rechazo de Injerto/tratamiento farmacológico , Quinasas Janus/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirroles/síntesis química , Animales , Proteínas Sanguíneas/metabolismo , Células CACO-2 , Línea Celular Tumoral , Permeabilidad de la Membrana Celular , Proliferación Celular/efectos de los fármacos , Monoterpenos Ciclohexánicos , Perros , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Humanos , Técnicas In Vitro , Activación de Linfocitos/efectos de los fármacos , Macaca fascicularis , Masculino , Modelos Moleculares , Monoterpenos/síntesis química , Monoterpenos/farmacocinética , Monoterpenos/farmacología , Piperidinas/síntesis química , Piperidinas/farmacocinética , Piperidinas/farmacología , Unión Proteica , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Distribución TisularRESUMEN
A mild, high-yielding, and practical protocol for the direct amidation of alkyl cyanoacetates using DBU is presented. This method eliminates the need for activation of cyanoacetic acid and/or high temperatures. It has been applied to the large-scale synthesis of CP-690,550-10 (1), a compound under development for the treatment of autoimmune diseases.
Asunto(s)
Acetatos/química , Amidas/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Inmunosupresores/síntesis química , Pirimidinas/síntesis química , Pirroles/síntesis química , Catálisis , Técnicas Químicas Combinatorias , Inmunosupresores/química , Inmunosupresores/farmacología , Estructura Molecular , Piperazinas/química , Pirimidinas/química , Pirimidinas/farmacología , Pirroles/química , Pirroles/farmacologíaRESUMEN
The synthesis, biological activity, and pharmacokinetic profile of CCR1 antagonists are described.
Asunto(s)
Piperazinas/química , Piperazinas/metabolismo , Receptores de Quimiocina/antagonistas & inhibidores , Animales , Perros , Haplorrinos , Humanos , Microsomas Hepáticos/metabolismo , Piperazinas/síntesis química , Ratas , Receptores CCR1RESUMEN
The present manuscript details structure-activity relationship studies of lead structure 1, which led to the discovery of CCR1 antagonists >100-fold more potent than 1.
Asunto(s)
Receptores de Quimiocina/antagonistas & inhibidores , Línea Celular , Humanos , Receptores CCR1 , Relación Estructura-ActividadRESUMEN
The synthesis, biological activity, and pharmacokinetic profile of novel CCR1 antagonists are described.
Asunto(s)
Receptores de Quimiocina/antagonistas & inhibidores , Animales , Perros , Haplorrinos , Farmacocinética , Receptores CCR1RESUMEN
The chemokines CCL3 and CCL5, as well as their shared receptor CCR1, are believed to play a role in the pathogenesis of several inflammatory diseases including rheumatoid arthritis, multiple sclerosis, and transplant rejection. In this study we describe the pharmacological properties of a novel small molecular weight CCR1 antagonist, CP-481,715 (quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(3-fluorobenzyl)-2(S),7-dihydroxy-7-methyloctyl]amide). Radiolabeled binding studies indicate that CP-481,715 binds to human CCR1 with a Kd of 9.2 nm and displaces 125I-labeled CCL3 from CCR1-transfected cells with an IC50 of 74 nm. CP-481,715 lacks intrinsic agonist activity but fully blocks the ability of CCL3 and CCL5 to stimulate receptor signaling (guanosine 5'-O-(thiotriphosphate) incorporation; IC50 = 210 nm), calcium mobilization (IC50 = 71 nm), monocyte chemotaxis (IC50 = 55 nm), and matrix metalloproteinase 9 release (IC50 = 54 nm). CP-481,715 retains activity in human whole blood, inhibiting CCL3-induced CD11b up-regulation and actin polymerization (IC50 = 165 and 57 nm, respectively) on monocytes. Furthermore, it behaves as a competitive and reversible antagonist. CP-481,715 is >100-fold selective for CCR1 as compared with a panel of G-protein-coupled receptors including related chemokine receptors. Evidence for its potential use in human disease is suggested by its ability to inhibit 90% of the monocyte chemotactic activity present in 11/15 rheumatoid arthritis synovial fluid samples. These data illustrate that CP-481,715 is a potent and selective antagonist for CCR1 with therapeutic potential for rheumatoid arthritis and other inflammatory diseases.
Asunto(s)
Inflamación , Quinoxalinas/química , Quinoxalinas/farmacología , Receptores de Quimiocina/antagonistas & inhibidores , Actinas/metabolismo , Artritis Reumatoide/metabolismo , Antígeno CD11b/biosíntesis , Calcio/metabolismo , Línea Celular , Quimiocinas/metabolismo , Quimiotaxis , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Cinética , Ligandos , Metaloproteinasa 9 de la Matriz/metabolismo , Modelos Químicos , Monocitos/metabolismo , Unión Proteica , Receptores CCR1 , Receptores de Quimiocina/metabolismo , Transducción de Señal , Transfección , Regulación hacia ArribaRESUMEN
Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.