Discovery of benzimidazole analogs as a novel interleukin-5 inhibitors.

A series of novel hydroxyethylaminomethylbenzimidazole analogs 5a-y were synthesized and evaluated for their IL-5 inhibitory activity using pro-B Y16 cell line. Among them, 2-(((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)amino)butan-1-ol (5e, 94.3% inhibition at 30 μM, IC = 3.5 μM, cLogP = 4.132) and 3-cyclohexyl-2-(((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)amino) propan-1-ol (5k, 94.7% inhibition at 30 μM, IC = 5.0 μM, cLogP = 6.253) showed the most potent inhibitory activity. The essential feature of SAR (Fig. 5) indicated that the chromenone ring can be replaced by a benzimidazole ring to maintain the inhibitory activity. In addition, the hydroxyethylaminomethyl group was suitable for the IL-5 inhibitory activity. Moreover, the hydrophobic substituents on carbon play an important role in the IL-5 inhibitory activity of these analogs. However, N-substituted analogs did not improve inhibitory activity. In addition, MTT assay of 5e and 5k with normal B lymphoblasts revealed that they had no significant effects on cell viability.