- Discovery and optimization of selective and in vivo active inhibitors of the lysophosphatidylserine lipase α/β-hydrolase domain-containing 12 (ABHD12)
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ABHD12 is a membrane-bound hydrolytic enzyme that acts on the lysophosphatidylserine (lyso-PS) and lysophosphatidylinositol (lyso-PI) classes of immunomodulatory lipids. Human and mouse genetic studies point to a key role for the ABHD12-(lyso)-PS/PI pathway in regulating (neuro)immunological functions in both the central nervous system and periphery. Selective inhibitors of ABHD12 would offer valuable pharmacological probes to complement genetic models of ABHD12-regulated (lyso)-PS/PI metabolism and signaling. Here, we provide a detailed description of the discovery and activity-based protein profiling (ABPP) guided optimization of reversible thiourea inhibitors of ABHD12 that culminated in the identification of DO264 as a potent, selective, and in vivo active ABHD12 inhibitor. We also show that DO264, but not a structurally related inactive control probe (S)-DO271, augments inflammatory cytokine production from human THP-1 macrophage cells. The in vitro and in vivo properties of DO264 designate this compound as a suitable chemical probe for studying the biological functions of ABHD12-(lyso)-PS/PI pathways.
- Ogasawara, Daisuke,Ichu, Taka-Aki,Jing, Hui,Hulce, Jonathan J.,Reed, Alex,Ulanovskaya, Olesya A.,Cravatt, Benjamin F.
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supporting information
p. 1643 - 1656
(2019/02/19)
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- Janus-type dendritic organoiridium (III) complex bearing holeand electron-transporting moieties: Synthesis, luminescence properties, and OLED applications
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A novel tris-cyclometalated iridium(III) complex bearing carbazole-based hole-transporting and triarylphosphine oxidebased electron-transporting dendrons was synthesized through a convergent synthetic route, and its facial and meridional isomers were isol
- Okamura, Naoki,Maeda, Takeshi,Yagi, Shigeyuki
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supporting information
p. 1419 - 1428
(2018/09/21)
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- Low catalyst loadings for copper-catalyzed O-arylation of phenols with aryl and heteroaryl halides under mild conditions
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A practical and mild strategy has been developed for the cross-coupling of O-arylation of phenol with differently substituted aryl halides and heteroaryl iodides using low catalyst loading of copper iodide under low operating temperature in DMF with TMHD as the ligand and Cs2CO3 as the base. This method tolerates a variety of functional groups including sterically hindered phenols and heteroaryl iodides to afford products in good to excellent yields (up to 95%). Georg Thieme Verlag Stuttgart. New York.
- Yong, Fui-Fong,Teo, Yong-Chua,Yan, Yaw-Kai,Chua, Guan-Leong
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supporting information; experimental part
p. 101 - 106
(2012/02/03)
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- GLUCOKINASE ACTIVATORS
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Provided are compounds of formula I that are useful in the treatment and/or prevention of diseases mediated by deficient levels of glucokinase activity, such as diabetes mellitus. Also provided are methods of treating or preventing diseases and disorders characterized by underactivity of glucokinase or which can be treated by activating glucokinase. (Formula I) wherein R2, L, Z, Y, G and R1 are as defined in the claims.
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Page/Page column 84-85
(2008/06/13)
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- Synthesis and biological activity of novel substituted pyridines and purines containing 2,4-thiazolidinedione
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A series of substituted pyridines and purines containing 2,4-thiazolidinedione were designed and synthesized from their corresponding pyridines and purines. These synthesized compounds (entry no. 6a-d, 12a-e, 18a-d, 23a-c) were evaluated for their effect on triglyceride accumulation in 3T3-L1 cells in vitro and their hypoglycemic and hypolipidemic activity in the genetically diabetic KKAy mice in vivo. On the basis of their biological activities, 5-(4-{2-[N-methyl-(5-phenyl-pyridin-2-yl)amino]ethoxy} benzyl)thiazolidine-2,4-dione (6d) was selected as a candidate for further pharmacological studies.
- Kim, Bok Young,Ahn, Joong Bok,Lee, Hong Woo,Kang, Sung Kwon,Lee, Jung Hwa,Shin, Jae Soo,Ahn, Soon Kil,Hong, Chung Il,Yoon, Seung Soo
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p. 433 - 447
(2007/10/03)
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- Stabilised 2,3-pyridyne reactive intermediates of exceptional dienophilicity
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The enhanced dienophilicity of 4-methoxy, 4-aryloxy and 4-thiophenoxy analogues 6-9 of 2,3-pyridyne (2) relative to 2 itself is reported. The regioselective lithiation of 4-alkoxy-(22, 23 and 25) and 4-thiophenoxy-2- chloropyridme (24) at low temperatures, followed by elimination of lithium chloride affords 4-alkoxy- and 4-thiophenoxypyridynes, which can be trapped in situ in a [4+2] cycloaddition reaction with furan to give endoxides 28-31 in moderate to good yields (25-58%). In contrast, precursors with a hydrogen (18) or methyl (12) substituent at C-4 give no evidence for pyridyne formation under these conditions. Attempts to generate 6-isopropoxy-2,3-pyridyne (10) from the low-temperature lithiation of 2-chloro-6-isopropoxypyridine were unsuccessful due to the instability of the 2-chloro-6-isopropoxy-5-lithiopyridine. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Connon, Stephen J.,Hegarty, Anthony F.
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p. 3477 - 3483
(2007/10/03)
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- Diels-Alder cycloadditions of stabilised 2,3-pyridynes
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Investigation of electron donating substituents at C-4 on 2,3-pyridyne 1 stability has revealed a novel stabilisation of these reactive species by aryloxy and thiophenoxy groups leading to a relatively high yielding [4+2] cycloaddition between 4-(p-methoxyphenoxy)-2,3-pyridine and furan at low temperature.
- Connon, Stephen J.,Hegarty, Anthony F.
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p. 735 - 737
(2007/10/03)
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