1015077-06-1Relevant articles and documents
Discovery of Potent Human Glutaminyl Cyclase Inhibitors as Anti-Alzheimer’s Agents Based on Rational Design
Hoang, Van-Hai,Tran, Phuong-Thao,Cui, Minghua,Ngo, Van T. H.,Ann, Jihyae,Park, Jongmi,Lee, Jiyoun,Choi, Kwanghyun,Cho, Hanyang,Kim, Hee,Ha, Hee-Jin,Hong, Hyun-Seok,Choi, Sun,Kim, Young-Ho,Lee, Jeewoo
supporting information, p. 2573 - 2590 (2017/04/03)
Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating the N-terminal pyroglutamate of β-amyloid peptides (pGlu-Aβ) and thus may participate in the pathogenesis of Alzheimer’s disease (AD). We designed a library of glutamyl cyclase (QC) inhibitors based on the proposed binding mode of the preferred substrate, Aβ3E?42. An in vitro structure-activity relationship study identified several excellent QC inhibitors demonstrating 5- to 40-fold increases in potency compared to a known QC inhibitor. When tested in mouse models of AD, compound 212 significantly reduced the brain concentrations of pyroform Aβ and total Aβ and restored cognitive functions. This potent Aβ-lowering effect was achieved by incorporating an additional binding region into our previously established pharmacophoric model, resulting in strong interactions with the carboxylate group of Glu327 in the QC binding site. Our study offers useful insights in designing novel QC inhibitors as a potential treatment option for AD.
Structure-based design of novel 2-amino-6-phenyl-pyrimido[5′, 4′:5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones as potent and orally active inhibitors of lymphocyte specific kinase (Lck): Synthesis, SAR, and in vivo anti-inflammatory activity
Martin, Matthew W.,Newcomb, John,Nunes, Joseph J.,Boucher, Christina,Chai, Lilly,Epstein, Linda F.,Faust, Theodore,Flores, Sylvia,Gallant, Paul,Gore, Anu,Gu, Yan,Hsieh, Faye,Huang, Xin,Kim, Joseph L.,Middleton, Scot,Morgenstern, Kurt,Oliveira-dos-Santos, Antonio,Patel, Vinod F.,Powers, David,Rose, Paul,Tudor, Yanyan,Turci, Susan M.,Welcher, Andrew A.,Zack, Debra,Zhao, Huilin,Zhu, Li,Zhu, Xiaotian,Ghiron, Chiara,Ermann, Monika,Johnston, David,Saluste, Carl-Gustaf Pierre
, p. 1637 - 1648 (2008/12/22)
Lck, or lymphocyte specific kinase, is a cytoplasmic tyrosine kinase of the Src family expressed in T-cells and NK cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T-cell receptor-mediated signaling, leading to normal T-cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the structure-guided design, synthesis, structure-activity relationships, and pharmacological characterization of 2-amino-6-phenylpyrimido[5′,4′:5,6]pyrimido[1,2- a]benzimidazol-5(6H)-ones, a new class of compounds that are potent inhibitors of Lck. The most promising compound of this series, 6-(2,6-dimethylphenyl)-2- ((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5′,4′:5,6] pyrimido-[1,2-a]benzimidazol-5(6H)-one (25), exhibits potent inhibition of Lck kinase activity. This activity translates into inhibition of in vitro cell-based assays and in vivo models of T-cell activation and arthritis, respectively.
