Structure-Activity Relationship Studies of Pyrimido[5,4-b]indoles as Selective Toll-Like Receptor 4 Ligands

摘要

Previous high throughput screening studies led to the discovery of two novel, nonlipid-like chemotypes as Toll-like receptor 4 (TLR4) agonists. One of these chemotypes, the pyrimido[5,4-b]indoles, was explored for structure activity relationship trends relative to production of TLR4 dependent cytokines/chemokines, resulting in a semioptimized lead (compound 1) that provided a starting point for further optimization studies. In this report, compounds belonging to three areas of structural modification were evaluated for biological activity using murine and human TLR4 reporter cells, primary murine bone marrow derived dendritic cells, and human peripheral blood mononuclear cells. The compounds bearing certain aryl groups at the C8 position, such as phenyl (36) and beta-naphthyl (39), had potencies significantly greater than compound 1. Compound 36 displayed human TLR4 agonist activity at submicromolar concentrations. The computational analysis suggests that the improved potency of these C8-aryl derivatives may be the result of additional binding interactions at the interface of the TLR4/myeloid differentiation protein-2 (MD-2) complex.