GSK180 是 kynurenine-3-monooxygenase (KMO) 的选择性、竞争性和强效抑制剂，KMO 是色氨酸代谢的关键酶 (IC50, ~6 nM)，但对色氨酸途径上的其他酶的活性可忽略不计。
GSK180 is a potent, selective and competitive inhibitor of kynurenine-3-monooxygenase (KMO) with an IC50 of ~6 nM. [1]
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GSK180 inhibited endogenous KMO action in primary human hepatocytes with similar potency (IC50 = 2.6 μM). GSK180 is proper for i.v. administration. GSK180 inhibited rat KMO mildly less potently than it did the human enzyme with an IC50 of 7 μM. GSK180 exhibited a concentration-dependent displacement of tryptophan from plasma proteins. [1]
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GSK180 was dosed to Kmowt and Kmonull mice as a bolus injection at 30 mg/kg, which delivered plasma levels 1 h after dosage of 263 ± 98 μM and 351 ± 87 μM, respectively. GSK180 resulted in a promotion in kynurenine in Kmowt mice, but no change was detected in the Kmonull mice, which confirms that this increase results from the inhibition of KMO. GSK180 caused an evident reduction in circulating tryptophan levels in both Kmowt and Kmonull mice, suggesting that the chemical had an additional effect unrelated to KMO inhibition. GSK180 is excepted from rat erythrocytes (blood:plasma ratio of 0.46), and it is modestly bound to rat plasma proteins (free fraction 7.7% at 1 mM, n = 2), meaning that the top free drug levels in plasma (92 μM) are >12-fold above the IC50 in cells. Treatment with GSK180 resulted in a rapid promotion in the circulating levels of both kynurenine and kynurenic acid, which restablished to baseline as the drug levels dropped. The fierce inflammatory cell infiltrate in AP consisted of MPO-positive neutrophils and monocytes positive for the ED1 antigen, the rat ortholog of CD68, which were present to the same extent in the pancreas tissue of rats with induced AP and rats with induced AP treated with GSK180. [1]
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Reference:
[1]. Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis.Nat Med. 2016 Feb;22(2):202-9.
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