RESUMEN
The structure-human CXCR3 binding affinity relationship of a series of pyridyl/pyrazinyl-piperazinyl-piperidine derivatives were explored with a focus to improve PK, hERG and metabolic profiles. Several small heterocycles were identified as amide surrogates, which minimized many potential metabolite issues. During the course of SAR development, we have observed the additive effect of desirable functional groups to improve hERG and PK profiles which lead to the discovery of many clinically developable CXCR3 antagonists with excellent overall profile.
Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Canales de Potasio Éter-A-Go-Go/metabolismo , Compuestos Heterocíclicos/farmacología , Receptores CXCR3/antagonistas & inhibidores , Amidas/administración & dosificación , Amidas/química , Animales , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/química , Humanos , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
The SAR of a novel pyrazinyl-piperazinyl-piperidine scaffold with CXCR3 receptor antagonist activity was explored. Optimization of the DMPK profile and reduction of hERG inhibition is described. Compound 16e with single-digit CXCR3 affinity, good rat PK and hERG profiles has been identified as a lead for further study.
Asunto(s)
Piperazinas/química , Pirazinas/química , Receptores CXCR3/antagonistas & inhibidores , Animales , Concentración 50 Inhibidora , Estructura Molecular , Piperazinas/farmacología , Unión Proteica/efectos de los fármacos , Pirazinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The structure-human CXCR3 binding affinity relationship of a series of pyridyl-piperazinyl-piperidine derivatives was explored. The optimization campaign highlighted the pronounced effect of 2'-piperazine substitution on CXCR3 receptor affinity. Analog 18j, harboring a 2'(S)-ethylpiperazine moiety, exhibited a human CXCR3 IC(50) of 0.2 nM.
Asunto(s)
Piperazinas/síntesis química , Piperidinas/síntesis química , Piridinas/síntesis química , Receptores CXCR3/agonistas , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Piperazina , Piperazinas/química , Piperazinas/farmacología , Piperidinas/química , Piperidinas/farmacología , Piridinas/química , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
A novel series of adenosine A(2A) receptor antagonists was identified by high-throughput screening of an encoded combinatorial compound collection. The initial hits were optimized for A(2A) binding affinity, A(1) selectivity, and in vitro microsomal stability generating orally available 2-aminoimidazo[4,5-b]pyridine-based A(2A) antagonist leads.
Asunto(s)
Pirimidinas/farmacología , Receptor de Adenosina A2A/efectos de los fármacos , Descubrimiento de Drogas , Humanos , Enlace de Hidrógeno , Microsomas/efectos de los fármacos , Receptor de Adenosina A2A/químicaRESUMEN
OBJECTIVE: All gamma-chain cytokines signal through JAK-3 and JAK-1 acting in tandem. We undertook this study to determine whether the JAK-3 selective inhibitor WYE-151650 would be sufficient to disrupt cytokine signaling and to ameliorate autoimmune disease pathology without inhibiting other pathways mediated by JAK-1, JAK-2, and Tyk-2. METHODS: JAK-3 kinase selective compounds were characterized by kinase assay and JAK-3-dependent (interleukin-2 [IL-2]) and -independent (IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF]) cell-based assays measuring proliferation or STAT phosphorylation. In vivo, off-target signaling was measured by IL-22- and erythropoietin (EPO)-mediated models, while on-target signaling was measured by IL-2-mediated signaling. Efficacy of JAK-3 inhibitors was determined using delayed-type hypersensitivity (DTH) and collagen-induced arthritis (CIA) models in mice. RESULTS: In vitro, WYE-151650 potently suppressed IL-2-induced STAT-5 phosphorylation and cell proliferation, while exhibiting 10-29-fold less activity against JAK-3-independent IL-6- or GM-CSF-induced STAT phosphorylation. Ex vivo, WYE-151650 suppressed IL-2-induced STAT phosphorylation, but not IL-6-induced STAT phosphorylation, as measured in whole blood. In vivo, WYE-151650 inhibited JAK-3-mediated IL-2-induced interferon-gamma production and decreased the natural killer cell population in mice, while not affecting IL-22-induced serum amyloid A production or EPO-induced reticulocytosis. WYE-151650 was efficacious in mouse DTH and CIA models. CONCLUSION: In vitro, ex vivo, and in vivo assays demonstrate that WYE-151650 is efficacious in mouse CIA despite JAK-3 selectivity. These data question the need to broadly inhibit JAK-1-, JAK-2-, or Tyk-2-dependent cytokine pathways for efficacy.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Janus Quinasa 3/antagonistas & inhibidores , Análisis de Varianza , Animales , Artritis Experimental/metabolismo , Western Blotting , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Janus Quinasa 3/metabolismo , Ratones , Ratones Endogámicos BALB C , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-gamma (INF-gamma) production.
Asunto(s)
Bencimidazoles/farmacología , Inhibidores Enzimáticos/farmacología , Janus Quinasa 3/antagonistas & inhibidores , Purinas/farmacología , Animales , Bencimidazoles/síntesis química , Bencimidazoles/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Interferón gamma/biosíntesis , Interleucina-2/antagonistas & inhibidores , Ratones , Modelos Animales , Modelos Moleculares , Estructura Molecular , Purinas/síntesis química , Purinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of trisubstituted purinones was synthesized and evaluated as A(2A) receptor antagonists. The A(2A) structure-activity relationships at the three substituted positions were studied and selectivity against the A(1) receptor was investigated. One antagonist 12o exhibits a K(i) of 9nM in an A(2A) binding assay, a K(b) of 18nM in an A(2A) cAMP functional assay, and is 220-fold selective over the A(1) receptor.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Purinonas/síntesis química , Animales , Humanos , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Purinonas/metabolismo , Purinonas/farmacología , Ratas , Receptor de Adenosina A2A/metabolismo , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
An encoded combinatorial library based on aryl and biaryl piperidine scaffolds was designed and synthesized. Screening of this library resulted in the discovery of high-nanomolar biaryl piperidine-based MCH1 receptor antagonists. Follow-up optimization using a parallel synthesis provided potent, single digit nanomolar antagonists.