RESUMEN
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 the discovery and early fundamental structure-activity relationship studies involving compound 3, a novel hydroxyethylene peptide isostere derived molecule that provides micromolar inhibition of CCL3 binding to its receptor CCR1. Initial studies established this screening hit as a legitimate lead for further medicinal chemistry optimization.
Asunto(s)
Péptidos/farmacología , Receptores de Quimiocina/antagonistas & inhibidores , Cristalografía por Rayos X , Péptidos/química , Conformación Proteica , 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.