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 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
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
High-throughput screening of an encoded combinatorial aryl piperazine library led to the identification of a novel series of potent piperazinyl-piperidine based CXCR3 antagonists. Analogs of the initial hit were synthesized via solid and solution phase methods to probe the influence of structure on the CXCR3 binding of these molecules. Various functional groups were found to contribute to the overall potency and essential molecular features were identified.