KT109

KT109 is a potent and an isoform-selective inhibitor of diacylglycerol lipase-β (DAGLβ) with an IC₅₀ of 42 nM. KT109 has ~60-fold selectivity for DAGLβ over DAGLα. KT109 shows inhibitory activity against PLA2G7 (IC₅₀=1 µM). KT109 shows negligible activity against FAAH, MGLL, ABHD11, and cytosolic phospholipase A2 (cPLA2 or PLA2G4A). KT109 perturbs a lipid network involved in macrophage inflammatory responses and lowers 2-Arachidonoylglycerol (HY-W011051), Arachidonic acid (HY-109590) and eicosanoids in mouse peritoneal macrophages^[1]. In Vitro:KT109 (0.1-100 nM in Neuro 2A, 0.001-10 μM in PC3; 4 h) inactivates DAGLβ in Neuro2A and PC3 cells with IC₅₀ values of 14 nM and 0.58 μM, respectively^[1].
KT109 (50 nM in Neuro 2A, 100 nM in PC3, 4 h) shows a marked reduction in cellular 2-AG (~90%), and arachidonic acid (AA), and increases SAG in Neuro2A and PC3 cells^[1].
In Vivo:KT109 (0.1-10 mg/kg; i.p.; 4 h) inhibits DAGLβ in mice with good potency and selectivity, exhibiting cross-reactivity with only a handful of additional serine hydrolases in macrophages^[1].
KT109 (5 mg/kg; i.p.; 4 h) lowers 2-AG, as well as Arachidonic acid (HY-109590) and eicosanoids, in mice peritoneal macrophages. KT109 reduces secreted TNF-α levels in lipopolysaccharide-stimulated macrophages^[1].
KT109 (1.6-40 mg/kg; i.p.) reverses the allodynic responses of Lipopolysaccharides (HY-D1056) (LPS)-treated paw, but i.c.v. or i.t. administration of KT109 do not alter LPS-induced allodynia in C57BL/6J mice^[2].
Repeated KT109 (40 mg/kg; i.p.; once daily for 6 days) administration prevents the expression of LPS-induced allodynia, without evidence of tolerance in C57BL/6J mice^[2].
KT109 reverses allodynia in the chronic constrictive injury (CCI) (40 mg/kg) and chemotherapy-induced neuropathic pain (CINP) (1.6-40 mg/kg) models and lacks discernible side effects in C57BL/6J mice^[2].