DO-264

• CAT Number: I019705
• CAS Number: 2301866-59-9
• Molecular Formula: C23H20Cl2F3N5O2S
• Molecular Weight: 558.40
• Purity: ≥95%
• Synonyms: 1-[1-[3-chloro-4-[2-chloro-4-(trifluoromethoxy)phenoxy]pyridin-2-yl]piperidin-4-yl]-3-pyridin-3-ylthiourea
• InChI: InChI=1S/C23H20Cl2F3N5O2S/c24-17-12-16(35-23(26,27)28)3-4-18(17)34-19-5-9-30-21(20(19)25)33-10-6-14(7-11-33)31-22(36)32-15-2-1-8-29-13-15/h1-5,8-9,12-14H,6-7,10-11H2,(H2,31,32,36)
• InChIKey: PIEQDBPBBQPLPL-UHFFFAOYSA-N
• SMILES: C1CN(CCC1NC(=S)NC2=CN=CC=C2)C3=NC=CC(=C3Cl)OC4=C(C=C(C=C4)OC(F)(F)F)Cl

DO-264 is a selective and in vivo-active inhibitor of Abhydrolase Domain Containing 12 (ABHD12), with an IC50 of 11 nM.
DO-264 displays an IC50 value of 11 nM (9.6 nM-13 nM). DO-264 blocks lyso-PS hydrolysis activities of recombinant mouse and human ABHD12 in transfected HEK293T cell lysates (DO-264 IC50 values of ~30 and 90 nM against mouse and human ABHD12, respectively) and the ABHD12-dependent lyso-PS lipase activity of membrane lysates from mouse brain (IC50=2.8 nM, 2.4 nM-3.3 nM) and human THP-1 cells (IC50= 8.6 nM, 6.3 nM-12 nM)[1].
Mice treated with DO-264 display dose-dependent increases in brain lyso-PS and 20:4 PS content that are qualitatively similar to the changes observed in ABHD12–/– mice. DO-264-treated mice, however, show minimal impairment in auditory function following four weeks of drug exposure. Both ABHD12–/– and DO-264-treated mice display exacerbated immunopathology following infection with the lymphocytic choriomeningitis virus (LCMV) clone 13, resulting in severe inflammatory lung damage, heightened chemokine production, and, in some cases, death[1].

Reference

[1]. Ogasawara D, et al. Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo. Nat Chem Biol. 2018 Dec;14(12):1099-1108.
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