Methanone, (4-[1,1'-biphenyl]-4-yl-1H-1,2,3-triazol-1-yl)[2-(phenylMethyl)-1-piperidinyl]-

Product NameMethanone, (4-[1,1'-biphenyl]-4-yl-1H-1,2,3-triazol-1-yl)[2-(phenylMethyl)-1-piperidinyl]-
CAS1402612-55-8
MFC27H26N4O
MW422.52
EINECS
MOL File1402612-55-8.mol

Chemical Properties

Boiling point	637.3±53.0 °C(Predicted)
Density	1.19±0.1 g/cm3(Predicted)
storage temp.	2-8°C
solubility	DMF:10.0(Max Conc. mg/mL);23.67(Max Conc. mM) DMSO:10.0(Max Conc. mg/mL);23.67(Max Conc. mM)
pka	-1.02±0.70(Predicted)
form	powder
color	white to beige
InChI	1S/C27H26N4O/c32-27(30-18-8-7-13-25(30)19-21-9-3-1-4-10-21)31-20-26(28-29-31)24-16-14-23(15-17-24)22-11-5-2-6-12-22/h1-6,9-12,14-17,20,25H,7-8,13,18-19H2
InChIKey	JKJMWHULJIOKPJ-UHFFFAOYSA-N
SMILES	O=C(N1CCCCC1Cc2ccccc2)n3cc(nn3)-c4ccc(cc4)-c5ccccc5

Safety Information

WGK Germany	WGK 3
Storage Class	11 - Combustible Solids
Hazard Classifications	Acute Tox. 4 Oral Aquatic Chronic 4

Usage And Synthesis

Uses

KT109 is a potent and selective inhibitor ofDAGLβ.

Biochem/physiol Actions

KT109 is a potent and selective inhibitor of Diacylglycerol lipase DAGLβ. Diacylglycerol lipases DAGLα and DAGLβ are serine hydrolases that biosynthesize the endocannabinoid 2-arachidonoylglycerol (2-AG). A lack of selective inhibitors has hampered study of these lipases. KT109 is a potent and selective DAGLβ inhibitor with an IC50 of 42 nM, ~60-fold selectivity for DAGLβ over DAGLα, and negligible activity against FAAH, MGLL and ABHD11, other key enzymes involved in endocannabinoid signaling. KT109 shows some inhibitory activity against PLA2G7 (IC50 = 1 μM) but no inhibitory activity against cytosolic phospholipase A2 (cPLA2 or PLA2G4A). The main off target inhibition against ABHD6 (IC50 = 16 nM) can be controlled for by use of the related compound, KT195, a potent (IC50 = 10 nM) and selective ABHD6 inhibitor with negligible activity against DAGLβ. KT109 disrupts the lipid network involved in macrophage inflammatory responses, lowering 2-AG, as well as arachidonic acid and eicosanoids, in mouse peritoneal macrophages.

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].

Animal Model:	DAGL-β (-/-) and (+/+) on C57BL/6J mice (23-40 g) (injected with 2.5 μg LPS into the plantar surface of the right hind paw after the 5th dose.)^[2]
Dosage:	40 mg/kg
Administration:	Intraperitoneal injection (i.p.). once daily for 6 days
Result:	Repeated administration prevented the expression of LPS-induced allodynia, without evidence of tolerance.

Animal Model:	Daglb^+/+, Daglb^+/- and Daglb^-/- mice on C57BI/6 and 129/SvEv mixture background were first treated intraperitoneally (i.p.) with 4% (w/v) thioglycollate 4 d before to induce recruitment of macrophages to the peritoneal cavity^[1]
Dosage:	0.1, 0.5, 1, 5, 10 mg/kg
Administration:	Intraperitoneal injection (i.p.). 4 h
Result:	Completely inactivated DAGLβ at doses as low as 0.5 mg/kg body weight. Also inhibited ABHD6. Time-course studies revealed that produced complete inhibition of macrophage DAGLβ by 1 h after in vivo treatment, and this inhibition was maintained for > 16 h.

Animal Model:	Pla2g4a^+/+ and Pla2g4a^-/- mice on a BALB/c background and Daglb^+/+, Daglb^+/- and Daglb^-/- mice on C57BI/6 and 129/SvEv mixture background were first treated intraperitoneally (i.p.) with 4% (w/v) thioglycollate 4 d before to induce recruitment of macrophages to the peritoneal cavity^[1]
Dosage:	5 mg/kg
Administration:	Intraperitoneal injection (i.p.). 4 h
Result:	Marked decreases in 2-AG content in macrophages. Significant increases in the DAGLβ substrate SAG, and reductions in arachidonic acid and in the arachidonic acid-derived prostaglandins PGE2 and PGD2. Significantly reduced secreted TNF-α levels in lipopolysaccharide-stimulated macrophages, and this suppressive effect was also observed in macrophages from Daglb/ mice.

Animal Model:	DAGL-β (-/-) and (+/+) on C57BL/6J mice (23-40 g)^[2]
Dosage:	1.6, 2.5, 5, 20, 40 mg/kg
Administration:	Intraperitoneal injection (i.p.).
Result:	Reversed LPS-induced allodynia in wild-type mice in a dose-dependent manner, but does not further alter the anti-allodynic phenotype in DAGL-β (-/-) mice.

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