Ro 61-8048 is an orally active and selective inhibitor of Kynurenine 3-hydroxylase, with an IC50 value of 37nM[1]. Ro 61-8048 increases brain kynurenic acid synthesis by inhibiting Kynurenine 3-hydroxylase, and selectively reduces extracellular glutamate concentrations and decreases excitability in the basal ganglia[2]. Ro 61-8048 has been widely used as an adjunct to trypanocidal chemotherapy, helping to prevent or alleviate trypanosomiasis-associated inflammatory responses in animal models[3].
In vitro, Ro 61-8048 (10µM) treatment for 6 hours attenuated 100ng/ml lipopolysaccharide (LPS)-induced extracellular nitrite accumulation and TNF-α expression in BV2 cells[4]. Incubation with 1µM Ro 61-8048 for 3 hours inhibited the expression of multiple pro-inflammatory cytokines, including TNF-α, IL-1β, MCP-1, CXCL10, and IL-8, in Caco-2 cells stimulated with IL-1β (10 ng/ml)[5].
In vivo, a single intraperitoneal injection of Ro 61-8048 at a dose of 50mg/kg reduced ethanol intake and preference in a mouse model of alcohol abuse 30 minutes later[6]. A single intraperitoneal injection of Ro 61-8048 at a dose of 100mg/kg significantly mitigated dystonia severity and elevated kynurenic acid levels in the striatum, cerebellum, and brainstem of dtsz mutant hamsters within 1 hour[7]. Intraperitoneal injection of Ro 61-8048 at a dose of 50mg/kg/day for 4 consecutive weeks alleviated high-fat diet-induced body weight gain and liver injury, and inhibited apoptosis of liver tissue cells in mice[8].
References:[1] Röver S, Cesura A M, Huguenin P, et al. Synthesis and biochemical evaluation of N-(4-phenylthiazol-2-yl) benzenesulfonamides as high-affinity inhibitors of kynurenine 3-hydroxylase[J]. Journal of medicinal chemistry, 1997, 40(26): 4378-4385.
[2] Moroni F, Cozzi A, Carpendo R, et al. Kynurenine 3-mono-oxygenase inhibitors reduce glutamate concentration in the extracellular spaces of the basal ganglia but not in those of the cortex or hippocampus[J]. Neuropharmacology, 2005, 48(6): 788-795.
[3] Röver S, Cesura A M, Huguenin P, et al. Synthesis and biochemical evaluation of N-(4-phenylthiazol-2-yl) benzenesulfonamides as high-affinity inhibitors of kynurenine 3-hydroxylase[J]. Journal of medicinal chemistry, 1997, 40(26): 4378-4385.
[4] Garrison A M, Parrott J M, Tuñon A, et al. Kynurenine pathway metabolic balance influences microglia activity: Targeting kynurenine monooxygenase to dampen neuroinflammation[J]. Psychoneuroendocrinology, 2018, 94: 1-10.
[5] Shi Y, Luo S, Zhai J, et al. A novel causative role of imbalanced kynurenine pathway in ulcerative colitis: upregulation of KMO and KYNU promotes intestinal inflammation[J]. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2024, 1870(2): 166929.
[6] Gil de Biedma‐Elduayen L, Giménez‐Gómez P, Morales‐Puerto N, et al. Influx of kynurenine into the brain is involved in the reduction of ethanol consumption induced by Ro 61‐8048 after chronic intermittent ethanol in mice[J]. British Journal of Pharmacology, 2022, 179(14): 3711-3726.
[7] Hamann M, Sander S E, Richter A. Effects of the kynurenine 3-hydroxylase inhibitor Ro 61-8048 after intrastriatal injections on the severity of dystonia in the dtsz mutant[J]. European journal of pharmacology, 2008, 586(1-3): 156-159.
[8] Liu Y, Xing H, Zhou T, et al. Kynurenine 3‐hydroxylase Inhibitor RO 61‐8048 Alleviates Nonalcoholic Fatty Liver Disease in High‐Fat Diet‐Induced Obese Mice[J]. Journal of Biochemical and Molecular Toxicology, 2025, 39(9): e70511.