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

Abstract

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(6 H)-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(6 H)-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.

Easy synthesis of new series of pteridine analogs: di- and tetra-hydropyrimido[4,5-d]pyrimidines via 5-pyrimidinecarbaldehydes

“…The tetrahydropyrimidopyrimidines 4 were obtained in moderate to good yields and also fully characterized by spectroscopic and analytical data. From the spectroscopic data of compounds 4, the formation of the new tetrahydropyrimidine ring is clearly observed, for example in 1 H-NMR spectra; as in the case of compounds 3, the signals for NH largely disappear, there remaining just the N(8)-H, and substituents attached to C(7) are clearly observed, with the new C(7) appearing in the 13 C-NMR at 59-71 ppm. The reaction between 2c and acetone afforded an unexpected product, which was characterized as 4e.…”

“…IR spectra were recorded in KBr disks on a Bruker TENSOR 27 spectrophotometer at "Centro de Instrumentación Científico-Técnica (CICT) at Universidad de Jaén". 1 H and 13 C NMR spectra were recorded on a Bruker Avance 400 spectrophotometer (CICT) operating at 400 MHz and 100 MHz respectively, using CDCl 3 and DMSO-d 6 as solvents and tetramethylsilane as internal standard; the carbon type described p (primary), s (secondary), t (tertiary) and q (quaternary) at 13 C-NMR was done using DEPT-135 and 2D-NMR experiments. Mass spectra were run on a Shimadzu-GCMS 2010-DI-2010 spectrometer (equipped with a direct inlet probe) operating at 70 eV.…”

“…From the low-energy conformations obtained for both diasteromers R/R and R/S we calculated the shielding tensors using the GIAO approach 33,34 from the program Gaussian 03. 35 Our study also includes the calculation of 13 C-NMR chemical shift for the diasteroisomers (R/R; R/S; S/R and S/S) by using the gauge independent atomic orbital (GIAO) approximation.…”

“…[1][2][3][4] See Figure 1 for compounds with the pyrimido [4,5-d]pyrimidine scaffold that have been found to show pharmacological activity, such as antiplatelet, 5 tyrosine kinase inhibitor, [6][7][8] antifolate (I-II), 9 antibacterial (III-IV), 10,11 anti-inflammatory, 12 hepatoprotective (V) 13 and antiviral 14 properties. On account of the pharmaceutical interest in these compounds, the development of highthroughput methodologies for the synthesis of novel pyrimidine-fused heterocyclic scaffolds is in continuous expansion.…”

Cobalt‐Catalyzed Aerobic Oxidative Cyclization of 2‐Aminoanilines with Isonitriles: Facile Access to 2‐Aminobenzimidazoles

“…The copper-catalyzed intramolecular cyclization reactions of thioureas [15] or guanidines (Scheme 1b) [16] and the amination of aryl halides with guanidines (Scheme 1c) [17] eliminate the need for stoichiometric desulfurization agents. Other approaches enable the arylamination of 2-chlorobenzimidazoles either by Pd catalysis [18] or by high temperature [10,19] or high pressure [20] S N Ar protocols (Scheme 1d). Finally, transition-metal-free cyclization reactions using I 2 [21a,b] or hypervalent iodine [21c] based oxidants have also been developed.…”