685827-70-7Relevant articles and documents
Discovery and optimization of a series of small-molecule allosteric inhibitors of MALT1 protease
Lu, Tianbao,Connolly, Peter J.,Philippar, Ulrike,Sun, Weimei,Cummings, Maxwell D.,Barbay, Kent,Gys, Luc,Van Nuffel, Luc,Austin, Nigel,Bekkers, Mariette,Shen, Fang,Cai, Ann,Attar, Ricardo,Meerpoel, Lieven,Edwards, James
, (2019)
We describe a series of potent and highly selective small-molecule MALT1 inhibitors, optimized from a High-Throughput Screening hit. Advanced analogues such as compound 40 show high potency (IC50: 0.01 μM) in a biochemical assay measuring MALT1 enzymatic activity, as well as in cellular assays: Jurkat T cell activation (0.05 μM) and IL6/10 secretion (IC50: 0.10/0.06 μM) in the TMD8 B-cell lymphoma line. Compound 40 also inhibited cleavage of the MALT1 substrate RelB (IC50: 0.10 μM). Mechanistic enzymology results suggest that these compounds bind to the known allosteric site of the protease.
Synthesis and biological evaluation of direct thrombin inhibitors bearing 4-(piperidin-1-yl)pyridine at the P1 position with potent anticoagulant activity
De Candia, Modesto,Fiorella, Filomena,Lopopolo, Gianfranco,Carotti, Andrea,Romano, Maria Rosaria,Lograno, Marcello Diego,Martel, Sophie,Carrupt, Pierre-Alain,Belviso, Benny D.,Caliandro, Rocco,Altomare, Cosimo
, p. 8696 - 8711 (2013/12/04)
The design and synthesis of a new class of nonpeptide direct thrombin inhibitors, built on the structure of 1-(pyridin-4-yl)piperidine-4-carboxamide, are described. Starting from a strongly basic 1-amidinopiperidine derivative (6) showing poor thrombin (fIIa) and factor Xa (fXa) inhibition activities, anti-fIIa activity and artificial membrane permeability were considerably improved by optimizing the basic P1 and the X-substituted phenyl P4 binding moieties. Structure-activity relationship studies, usefully complemented with molecular modeling results, led us to identify compound 13b, which showed excellent fIIa inhibition (Ki = 6 nM), weak anti-Xa activity (K i = 5.64 μM), and remarkable selectivity over other serine proteases (e.g., trypsin). Compound 13b showed in vitro anticoagulant activity in the low micromolar range and significant membrane permeability. In mice (ex vivo), 13b demonstrated anticoagulant effects at 2 h after oral dosing (100 mg·kg-1), with a significant 43% prolongation of the activated partial thromboplastin time (aPTT), over controls (P 0.05).
1, 4-DISUBSTITUTED PIPERIDINES AS VASOPRESSIN RECEPTOR VIA ANTAGONISTS
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Page/Page column 44, (2010/09/17)
The present invention provides compounds of formula (1) compositions comprising such compounds; the use of such compounds in therapy (such as in the treatment of dysmenorrhoea); and methods of treating patients with such compounds; wherein A and G are as defined herein.