Novel amide and imidazole compounds as potent hematopoietic prostaglandin D2 synthase inhibitors

In seeking novel and potent small molecule hematopoietic prostaglandin D-2 synthase (H-PGDS) inhibitors as potential therapies for PGD(2)-mediated diseases and conditions, we explored a series comprising multiple aryl/heteroaryl rings attached in a linear arrangement. Each compound incorporates an amide or imidazole linker between the pyrimidine or pyridine core ring and the tail ring system. We synthesized and screened twenty analogs by fluorescence polarization binding assay, thermal shift assay, glutathione S-transferase inhibition assay, and a cell-based assay measuring suppression of LPS-induced PGD(2) stimulation. Amide analogs show ten-fold greater shift in the thermal shift assay in the presence of glutathione (GSH) versus the same assay run in the absence of GSH. The imidazole analogs did not produce a significant change in thermal shift between the two assay conditions, suggesting a possible stabilization effect of the amide linker in the synthase-GSH-inhibitor complex. Imidazole analog 23, (KMN-010034) demonstrates superior potency across the in vitro assays and good in vitro metabolic stability in both human and guinea pig liver microsomes.

Automated summary

By synthesizing and screening multiple analogs, it was found that the amide linker may play a stabilizing role in the H-PGDS inhibitor complex, while the imidazole analogs exhibited higher potency. One specific imidazole analog showed superior performance in vitro assays.