A parallel study reported on the possibility of replacing the benzimidazole with other heteroaromatic ring systems. In order to identify feasible alternative ring systems, various heteroaryl scaffolds with the distal amine side chain attached to the central nitrogen of AMD070 was explored . Most of the reported ring systems led to compounds endowed with noticeable antiviral activity. The isoquinoline derivatives 115 and 116 were particularly promising showing IC50 values of 12 and 11 nM, respectively. Subsequently, the isoquinoline scaffold of 115 was chosen for further study. As a result, the unsubstituted analogue 117 showed significant activity even lacking the amine side chain. The introduction of a 1-carbon primary amine moiety (compound 118) resulted in a significant increase in activity compared to compound 117. On the other hand, the dimethylation of the amino group led to a loss in activity (compound 119). The guanidine derivatives 120 and 128 showed remarkable activities and the best cytotoxicity profiles within the whole series. An interesting aspect of the SAR in this series of compounds was the unexpected high activity of the non-basic derivatives 121, 129 and 130. The dimethylaminoglycine analogue 122 was relatively potent with an IC50 of 12 nM. Proline derivatives 123 and 124 showed a consistent reduction in activity in both the enantiomeric forms. The 3-carbon amine derivative 127, with an IC50 of 5 nM, was the most active analogue among this series of compounds. The structures of derivatives 89-130 are shown in Figures -.
Representative examples of tetrahydroquinoline-based CXCR4 antagonists. IC50 values are the concentrations required to protect 50% of MT4 cells against X4 HIV-1 NL4.3 cytopathicity .
93. Cole E, Shao X, Fawaz M, Scott P. Radiosynthesis of [11C]PyrATP1, a novel radiotracer targeting the ATP-binding site of GSK-3β. 2014;55:1110
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Structure of quinoline based CXCR4 antagonists. EC50 values are the concentrations for 50% inhibition of the SDF-1α binding to CXCR4 receptor in HEK293 cells .
68. Tamamura H, Hiramatsu K, Ueda S, Wang Z, Kusano S, Terakubo S. . Stereoselective synthesis of [L-Arg-L/D-3-(2-naphthyl)alanine]-type (E)-alkene dipeptide isosteres and its application to the synthesis and biological evaluation of pseudopeptide analogues of the CXCR4 antagonist FC131. 2005;48:380-91
Using the predicted conformations of CXCR4, libraries of compounds have been screened to identify new antagonists . Among the top candidates, compound 213 (NSC56612) was selected as the lead compound by high-throughput screening. The inspection of several databases led to the identification of structural similarity between such lead and numerous quinoline or acridine derivatives, such as chloroquine, hydroxychloroquine and quinacrine. In order to identify the binding sites of these derivatives, chloroquine 214 and hydroxychloroquine 215 were docked onto to the crystal structure of CXCR4. The results suggested that the tertiary amine groups bind to D97 on TM2 and E32 in the amino terminus of CXCR4 through hydrogen bonds while aromatic residues Y45, W94, H113 and Y255 establish hydrophobic interactions with the aromatic counterpart of identified compounds.
Select examples of tetrahydroquinoline-based CXCR4 antagonists. IC50 values are the concentrations required to protect 50% MT4 cells against X4 HIV-1 NL4.3 cytopathicity .
146. Hicks JW, Wilson AA, Rubie EA, Woodgett JR, Houle S, Vasdev N. Towards the preparation of radiolabeled 1-aryl-3-benzyl ureas: Radiosynthesis of [11C-carbonyl] AR-A014418 by [11C]CO2 fixation. 2012;22:2099-101