BX471 (ZK-811752)

BX471 (ZK811752, BAY 865047, SH T 04268H)은 강력한 비펩타이드성 CC chemokine receptor-1 (CCR1) 길항제로, CCR1이 형질감염된 HEK293 세포에 MIP-1α 및 MCP-3가 결합할 때 각각 1 nM 및 5.5 nM의 Ki 값을 가집니다.

강력한 길항제인 BX471은 CC chemokine receptor-1 (CCR1)에 대한 리간드 결합을 대체함으로써 CCR1에 의해 매개되는 효과를 억제할 수 있습니다. 또한 BX-471은 Treg 세포 집단을 증가시켜 항알레르기 효과를 나타냅니다.^{<a class="sref" href="#s_ref">[1]</a>}^{<a class="sref" href="#s_ref">[2]</a>}

금식견에서 BX471의 반감기는 약 3시간이었고, 경구 생체 이용률은 약 60%였습니다. EAE 모델 쥐에서 CCR1 길항제인 BX471은 질병의 심각도를 용량 의존적으로 감소시켰습니다.^{<a class="sref" href="#s_ref">[1]</a>}

• 세포주

  THP-1- or CCR1-transfected HEK293 cells

• 농도

  10 µM

• 배양 시간

  24 h

• 방법

  Binding assays were performed by filtration. Radiolabeled chemokines at a final concentration of approximately 0.1–0.2 nM were used as ligand. HEK293 cells expressing human CCR1 at 8,000 or 300,000 cells per assay point were used as the receptor source. Nonspecific binding was determined in the presence of 100 nM unlabeled chemokine. The binding data were curve-fitted with the computer program IGOR (Wavemetrics) to determine the affinity and number of sites. To demonstrate that CCR1 antagonism by BX 471 was not due to the cellular toxicity of the compound, THP-1- or CCR1-transfected HEK293 cells were treated with BX 471 at concentrations up to 10 µM for 24 h, and cellular toxicity was monitored by measuring WST-1 staining. No significant toxicity was observed.

• 동물 모델

  Fasted male beagle dogs; Male Lewis Rats of EAE model

• 용량

  4 mg/kg (for fasted male beagle dogs); 20 and 50 mg/kg (for Male Lewis Rats)

• 투여

  p.o.