*Purpose: The effect of ANG-3777, a small-molecule mimetic of hepatocyte growth factor, was evaluated on reducing ischemia-reperfusion-induced renal injury and mortality in rats and dogs subjected to normothermic renal ischemia and reperfusion (nRIR).

*Methods: In study 1, Sprague Dawley (SD) rats were subjected to 60-min renal ischemia and 24-hr reperfusion. ANG-3777 (2 mg/kg, intravenous [IV]; N=26) or vehicle (N=26) was given pre-‑ischemia and 18 hours post-reperfusion. At the onset of reperfusion, the contralateral (right) kidney was excised. Blood urea nitrogen (BUN) and creatinine (Cr) levels were assessed at 24 hrs pre-sacrifice. In study 2, SD rats were subjected to 60-min renal ischemia and 96-hr reperfusion and were dosed 24-hr post-onset of reperfusion then once daily (QD) x 96 hrs with ANG-3777 IV (0.2, N=48; or 2 mg/kg, N=15) or vehicle (N=70). Blood and urine were collected daily; mortality was recorded. In study 3, beagle dogs were subjected to 120-min renal ischemia and 7d reperfusion. For immediate treatment, dogs were dosed QD with ANG-3777 IV (10 mg/kg; N=4) or vehicle (N=4), and reperfusion was started. For delayed treatment, dogs were dosed QD with ANG-3777 IV (10 mg/kg; N=5) 1d post-ischemia-reperfusion. Dogs were dosed QD through Day 4. Renal function was assessed daily for 8d.

*Results: Following immediate ANG-3777 treatment, reduction in BUN was statistically significant (p<0.05) in male rats, whereas reduction in Cr was statistically significant (p<0.05) in male and female rats. For dogs initiating ANG-3777 24-hr post ischemic injury, treatment significantly reduced BUN and Cr (p<0.005) vs vehicle at all times and for both doses with exception of BUN at 48 hrs post‑reperfusion for the 0.2 mg/kg group. ANG-3777 (2 and 0.2 mg/kg) significantly increased urine output vs vehicle at 48, 72, and 96 hr post-reperfusion (p<0.001; Fig 1). Survival was significantly greater (p=0.035) at Day 4 for 0.2 mg/kg ANG-3777 (10 of 15; 67%) vs vehicle (24 of 70; 34%). In the dog model, immediate and delayed treatments with ANG-3777 reduced BUN and Cr (p<0.0001) vs vehicle.

*Conclusions: ANG-3777 attenuated renal dysfunction, increased urine output, and improved survival in animals subjected to nRIR. ANG-3777 was efficacious, both when administered at onset of ischemic injury and when initiated 1d post-ischemic injury.

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