- SAR development of lysine-based irreversible inhibitors of transglutaminase 2 for huntington's disease
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We report a series of irreversible transglutaminase 2 inhibitors starting from a known lysine dipeptide bearing an acrylamide warhead. We established new SARs resulting in compounds demonstrating improved potency and better physical and calculated properties. Transglutaminase selectivity profiling and in vitro ADME properties of selected compounds are also reported.
- Wityak, John,Prime, Michael E.,Brookfield, Frederick A.,Courtney, Stephen M.,Erfan, Sayeh,Johnsen, Siw,Johnson, Peter D.,Li, Marie,Marston, Richard W.,Reed, Laura,Vaidya, Darshan,Schaertl, Sabine,Pedret-Dunn, Anna,Beconi, Maria,MacDonald, Douglas,Mu?oz-Sanjuan, Ignacio,Dominguez, Celia
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supporting information
p. 1024 - 1028
(2013/02/22)
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- Discovery and optimization of a biphenylacetic acid series of prostaglandin D2 receptor DP2 antagonists with efficacy in a murine model of allergic rhinitis
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Biphenylacetic acid (5) was identified through a library screen as an inhibitor of the prostaglandin D2 receptor DP2 (CRTH2). Optimization for potency and pharmacokinetic properties led to a series of selective CRTH2 antagonists. Compounds demonstrated potency in a human DP2 binding assay and a human whole blood eosinophil shape change assay, as well as good oral bioavailability in rat and dog, and efficacy in a mouse model of allergic rhinitis following oral dosing.
- Scott, Jill M.,Baccei, Christopher,Bain, Gretchen,Broadhead, Alex,Evans, Jilly F.,Fagan, Patrick,Hutchinson, John H.,King, Christopher,Lorrain, Daniel S.,Lee, Catherine,Prasit, Peppi,Prodanovich, Pat,Santini, Angelina,Santini, Brian A.
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scheme or table
p. 6608 - 6612
(2011/12/04)
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- Dipeptidyl aspartyl fluoromethylketones as potent caspase inhibitors: SAR of the N-protecting group
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The synthesis and biological evaluation of a group of N-protected Val-Asp-fmk as caspase inhibitors is reported. This article describes the synthesis and biological evaluation of a group of N-protected Val-Asp-fmk as caspase inhibitors. The protecting group was found to contribute to caspase-3 inhibiting activity, and compounds with a large group such as Cbz are more active than compounds with a small group such as Ac. Compounds with more hydrophobic protecting groups were found to be more active in cell apoptosis protection assays, probably due to increased cell permeability. MX1122, 2,4-di-Cl-Cbz-Val-Asp-fmk, is identified as a potent broad-spectrum caspase inhibitor and is selective for caspases versus other proteases, with good activity in the cell apoptosis protection assays as well as good efficacy in the mouse liver apoptosis model.
- Cai, Sui Xiong,Guan, Lufeng,Jia, Shaojuan,Wang, Yan,Yang, Wu,Tseng, Ben,Drewe, John
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p. 5295 - 5300
(2007/10/03)
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- Caspase inhibitors and the use thereof
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The present invention is directed to novel dipeptide thereof, represented by the general Formula I: where R1-R3, X and Y are defined herein. The present invention also relates to the discovery that compounds having Formula I are pote
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- Non-phosgene synthesis of benzyl chloroformate (CbzCl)
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A novel synthetic method for benzyl chloroformate (CbzCl) using carbon monoxide or carbonyl sulfide as a carbonyl source was established. Benzyl chloroformate was successfully synthesized by the chlorination using sulfuryl chloride of S-methyl O-benzyl carbonothioate, which was prepared by the carbonylation of benzyl alcohol with carbon monoxide and sulfur (or carbonyl sulfide) in the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) followed by esterification using methyl iodide.
- Mizuno, Takumi,Takahashi, Junko,Ogawa, Akiya
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p. 7765 - 7767
(2007/10/03)
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- Benzyl chloroformate (CbzCl) synthesis using carbon monoxide as a carbonyl source
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A novel non-phosgene synthetic method for benzyl chloroformate (CbzCl) was established. S-Methyl O-benzyl carbonothioates were prepared by the carbonylation of benzyl alcohols with carbon monoxide and sulfur (or carbonyl sulfide) in the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) followed by esterification using methyl iodide in good yields. Then, CbzCl derivatives were successfully synthesized by the chlorination of S-methyl O-benzyl carbonothioates using sulfuryl chloride in excellent yields.
- Mizuno, Takumi,Takahashi, Junko,Ogawa, Akiya
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p. 10011 - 10015
(2007/10/03)
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- New Side-Chain Protecting Groups for Lysine and Tyrosine Suitable for Solid-Phase Peptide Synthesis
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The syntheses of two new lysine and tyrosine derivatives, Boc-Lys(2-ClZ) and Boc-Tyr(2-BrBzl) have been described.Their use in the solid-phase peptide synthesis of the decapeptide Glu-Arg(NO2)-Gly-Phe-Phe-Tyr-Thr-Pro-Lys-Thr (I) corresponding to the seque
- Salem, Ezzeldin M.,Schou, O.
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