381-63-5Relevant academic research and scientific papers
Haloacetamidine-based inactivators of protein arginine deiminase 4 (PAD4): Evidence that general acid catalysis promotes efficient inactivation
Knuckley, Bryan,Causey, Corey P.,Pellechia, Perry J.,Cook, Paul F.,Thompson, Paul R.
, p. 161 - 165 (2010)
Dysregulated protein arginine deiminase (PAD) activity, particularly PAD4, has been suggested to play a role in the onset and progression of numerous human diseases, including rheumatoid arthritis (RA). Given the potential role of PAD4 in RA, we set out to develop inhibitors/inactivators that could be used to modulate PAD activity and disease progression. This effort led to the discovery of two mechanism-based inactivators, denoted F- and Cl-amidine, that inactivate PAD4 by the covalent modification of an active-site cysteine that is critical for catalysis. To gain further insights into the mechanism of inactivation by these compounds, the effect of pH on the rates of inactivation was determined. These results, combined with the results of solvent isotope effect and proton inventory studies, strongly suggest that the inactivation of PAD4 by F- and Cl-amidine proceeds by a multistep mechanism that involves the protonation and stabilization of the tetrahedral intermediate formed upon nucleophilic attack by the active-site cysteine, that is, Cys645. Stabilization of this intermediate would help to drive the halide-displacement reaction, which results in the formation of a three-membered sulfonium ring that ultimately collapses to form the inactivated enzyme. This finding - that protonation of the tetrahedral intermediate is important for enzyme inactivation - also suggests that, during catalysis, protonation of the analogous intermediate is required for efficient substrate turnover.
DIPEPTIDYL PEPTIDASE-IV INHIBITING COMPOUNDS, METHODS OF PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AS AN ACTIVE AGENT
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Page/Page column 164, (2010/11/24)
The present invention relates to novel compounds exhibiting good inhibitory activity versus Dipeptidyl Peptidase-IV(DPP-IV), methods of preparing the same and pharmaceutical compositions containing the same as an active agent.
POLY(ADP-RIBOSE) POLYMERASE INHIBITORS CONSISTING OF PYRIMIDINE DERIVATIVES
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, (2008/06/13)
A medicament for therapeutic and/or preventive treatment of a brain disease, which comprises a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient: wherein R represents hydrogen atom, a C1-C8 alkyl group, a substituted C1-C8 alkyl group, an aryl group, a substituted aryl group, an aryl(C1-C8)alkyl group and the like; Y represents hydrogen atom or -C(R2)R3 (R2 and R3 represent hydrogen atom, a C1-C8 alkyl group, a C1-C8 alkoxy(C1-C8)alkyl group, a hydroxy(C1-C8)alkyl group and the like); symbol "a" represents single bond when Y represents hydrogen atom, or "a" represents double bound when Y represents -C(R2)R3; -A-B- represents -CH2-CH2-, -S-CH2-, -O-CH2-, -CH2-S-, -CH2-O-, -SO-CH2-, -CH2-SO-, -SO2-CH2-, or -CH2-SO2-; and Z represents -CH2- or single bond.
