19844-93-0Relevant articles and documents
Structure-based optimization of potent and selective inhibitors of the tyrosine kinase erythropoietin producing human hepatocellular carcinoma receptor B4 (EphB4)
Lafleur, Karine,Huang, Danzhi,Zhou, Ting,Caflisch, Amedeo,Nevado, Cristina
supporting information; experimental part, p. 6433 - 6446 (2010/03/31)
The tyrosine kinase EphB4 is an attractive target for drug design because of its recognized role in cancer-related angiogenesis. Recently, a series of commercially available xanthine derivatives were identified as micromolar inhibitors of EphB4 by high-throughput fragment-based docking into the ATP-binding site of the kinase domain. Here, we have exploited the binding mode obtained by automatic docking for the optimization of these EphB4 inhibitors by chemical synthesis. Addition of only two heavy atoms, methyl and hydroxyl groups, to compound 4 has yielded the single-digit nanomolar inhibitor 66, with a remarkable improvement of the ligand efficiency from 0.26 to 0.37 kcal/(mol per non-hydrogen atom). Compound 66 shows very high affinity for a few other tyrosine kinases with threonine as gatekeeper residue (Abl, Lck, and Src). On the other hand, it is selective against kinases with a larger gatekeeper. A 45 ns molecular dynamics (MD) simulation of the complex of EphB4 and compound 66 provides further validation of the binding mode obtained by fragment-based docking. 2009 American Chemical Society.
Imidazo[2,1-i]purin-5-ones and related tricyclic water-soluble purine derivatives: Potent A2A- and A3-adenosine receptor antagonistst
Müller, Christa E.,Thorand, Mark,Qurishi, Ramatullah,Diekmann, Martina,Jacobson, Kenneth A.,Padgett, William L.,Daly, John W.
, p. 3440 - 3450 (2007/10/03)
A series of tricyclic imidazo[2,1-i]purinones and ring-enlarged analogues derived from xanthine derivatives have been prepared as adenosine receptor (AR) antagonists. In comparison with xanthines, the tricyclic compounds exhibit increased water solubility due to a basic nitrogen atom, which can be protonated under physiological conditions. Substituents were introduced that confer high affinity for A2A or A3 ARs, respectively. A new capillary electrophoresis method was developed for the determination of the enantiomeric purity of selected chiral products using native and modified β-cyclodextrins as chiral discriminators. The compounds were investigated in radioligand binding assays at rat brain A1 and A2A ARs. Selected compounds were additionally investigated in radioligand binding assays at human recombinant A3 ARS and in functional studies (adenylate cyclase assays) at A1 ARs of rat fat cell membranes, A2A ARs of rat PC 12 cell membranes, and mouse A2B ARs of NIH 3T3 cell membranes. Structure-activity relationships were similar to those of corresponding xanthine derivatives. The 2-styrylimidazopurinones were less potent at A2A ARs as compared to 8-styrylxanthine derivatives. The most potent compound at A2A ARs was (S)-1,4-dimethyl-8-ethyl-2-styryl- imidazo[2,1-i]purinone (S-25) exhibiting a Ki value of 424 nM at rat A2A ARs. The compound was highly selective for A2A receptors vs A1 and A3 ARs. Selectivity vs A2B ARs, however, was low. Among the 1-unsubstituted 2-phenyl-imidazo[2,1-i]purin-5-one derivatives, very potent and highly selective antagonists for human A3 ARs were identified. The most potent A3 antagonist of the present series was (R)-4-methyl-8-ethyl-2-phenyl-imidazo[2,1-i]purin-5-one (R-24) exhibiting a Ki value of 2.3 nM and high selectivity for A3 receptors vs all other AR subtypes.
