KML 29 is reported to display IC50 values of 43, 15, and 5.9 nM toward rat, mouse, and human monoacylglycerol lipase (MAGL), respectively [1]. KML29 potently and selectively inhibited MAGL in vitro and in vivo with minimal cross-reactivity toward other central and peripheral serine hydrolases, including no detectable activity against FAAH [1].
KML 29 acted as a selective MAGL inhibitor showed antiproliferative activity against B16-F10 and HT-29 cells, while showed no significant effect on A431, H1975, OVCAR-3, HCC827, Hela and A549 cell lines [2].
KML 29 delays onset, progression and survival in the low-copy SOD1G93A Amyotrophic lateral sclerosis (ALS) mouse. oral administration of KML 29 is therapeutic by delaying onset, improving symptoms and extending lifespan, which was associated with increasing tissue levels of neurotrophic factors and decreasing pro-inflammatory cytokines [3]. Acute administration of KML 29 mostly increased 2-AG levels in fat, brain and spinal cord without any effect on AEA levels. KML 29 also reduced arachidonic acid levels in the CNS and peripheral organs [4].
References:
[1]. J.W. Chang, M.J. Niphakis, K.M. Lum, A.B. Cognetta 3rd, C. Wang, M.L. Matthews, S. Niessen, M.W. Buczynski, L.H. Parsons, B.F. Cravatt. Highly selective inhibitors of monoacylglycerol lipase bearing a reactive group that is bioisosteric with endocannabinoid substrates. Chem. Biol., 19 (2012), pp. 579-588
[2]. Deng H, Lei Q, Yang N, et al. Discover Monoacylglycerol Lipase Inhibitors by Combination of Fluorogenic Substrate Assay and Activity-Based Protein Profiling[J]. Frontiers in pharmacology, 2022: 3328.
[3]. N. Pasquarelli, M. Engelskirchen, J. Hanselmann, S. Endres, C. Porazik, H. Bayer, E. Buck, M. Karsak, P. Weydt, B. Ferger, A. Witting. Evaluation of monoacylglycerol lipase as a therapeutic target in a transgenic mouse model of ALS. Neuropharmacology, 124 (2017), pp. 157-169
[4]. N Pasquarelli, et al., Comparative biochemical characterization of the monoacylglycerol lipase inhibitor KML29 in brain, spinal cord, liver, spleen, fat and muscle tissue. Neuropharmacology 91, 148-156 (2015).
据报道，KML 29 对大鼠、小鼠和人单酰基甘油脂肪酶 (MAGL) 的 IC50 值分别为 43、15 和 5.9 nM [1]。 KML29 在体外和体内有效且选择性地抑制 MAGL，对其他中枢和外周丝氨酸水解酶的交叉反应最小，包括对 FAAH [1] 的可检测活性。
作为选择性 MAGL 抑制剂的 KML 29 对 B16-F10 和 HT-29 细胞显示出抗增殖活性，而对 A431、H1975、OVCAR-3、HCC827、Hela 和 A549 细胞系没有显着影响[2 ].
KML 29 延迟低拷贝 SOD1G93A 肌萎缩侧索硬化 (ALS) 小鼠的发病、进展和存活。口服 KML 29 具有延缓发作、改善症状和延长寿命的治疗作用，这与组织中神经营养因子水平的升高和促炎细胞因子的降低有关[3]。 KML 29 的急性给药主要增加脂肪、脑和脊髓中的 2-AG 水平，而对 AEA 水平没有任何影响。 KML 29 还降低了中枢神经系统和外周器官中的花生四烯酸水平[4]。