JNJ-27141491

JNJ-27141491 is a selective, noncompetitive and orally active functional antagonist of human CCR2[1].

Signaling Pathways >> GPCR/G Protein >> CCR

Signaling Pathways >> Immunology/Inflammation >> CCR

Research Areas >> Inflammation/Immunology

hCCR2

JNJ-27141491 抑制 MCP-1 诱导的 [35S]GTPγS 与 hCCR2-CHO 细胞膜的结合 (IC50=38±9 nM)，并减少 MCP-1 诱导的 Ca2+ 动员，在 hCCR2-CHO 细胞的 IC50 为 13±1 nM，在 THP-1 细胞的 IC50 为 13±2 nM 和在人血单核细胞的 IC50 为 43±4 nM。JNJ-27141491 也抑制人 PBMC 对 MCP-1 的趋化作用，其 IC50 值为 97±16 nM[1]。 JNJ-27141491 与 MCP-1 和 hCCR2 的结合竞争，并作为 CCR2 受体的非竞争性拮抗剂[1]。

JNJ-27141491 (5-40 mg/kg; oral; once or twice daily) 抑制单核细胞和中性粒细胞招募到转基因 hCCR2 敲入小鼠的肺泡空气空间[1]。 JNJ-27141491 (20 mg/kg; oral; daily for 16 days) 在转基因 CCR2 小鼠中延迟实验性自身免疫性脑脊髓炎 (EAE)[1]。 Animal Model: Transgenic mCCR2 knockout/hCCR2 knockin C57BL/6 mice[1] Dosage: 5, 10, 20, or 40 mg/kg Administration: Oral, once or twice daily Result: Once-daily oral treatment with 40, 20, 10, or 5 mg/kg inhibited the monocyte influx with 77, 57, 49, and 27%, respectively, compared with vehicle treatment, whereas this value was 74 and 22% after twice-daily oral treatment with 20 or 5 mg/kg. The neutrophil influx was also reduced; neutrophil numbers were decreased, with 56, 45, 20, and 8% after 40, 20, 10, or 5 mg/kg q.d. treatments and with 45 and 20% after 20 and 5 mg/kg b.i.d. treatments.

[1]. Buntinx M, et al. Pharmacological profile of JNJ-27141491 [(S)-3-[3,4-difluorophenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxyl acid methyl ester], as a noncompetitive and orally active antagonist of the human chemokine receptor CCR2. J Pharmacol Exp Ther. 2008 Oct;327(1):1-9.