Identification of Inhibitors of NOD1-Induced Nuclear Factor-κB Activation

Abstract

NOD1 (nucleotide-binding oligomerization domain 1) protein is a member of the NLR (NACHT and leucine rich repeat domain containing proteins) protein family, which plays a key role in innate immunity as a sensor of specific microbial components derived from bacterial peptidoglycans and induction of inflammatory responses. Mutations in NOD proteins have been associated with various inflammatory diseases that affect NF-κB (nuclear factor κB) activity, a major signaling pathway involved in apoptosis, inflammation, and immune response. A luciferase-based reporter gene assay was utilized in a high-throughput screening program conducted under the NIH-sponsored Molecular Libraries Probe Production Center Network program to identify the active scaffolds. Herein, we report the chemical synthesis, structure-activity relationship studies, downstream counterscreens, secondary assay data, and pharmacological profiling of the 2-aminobenzimidazole lead (compound 1c, ML130) as a potent and selective inhibitor of NOD1-induced NF-κB activation.

Figure 1

Three scaffolds (IC₅₀ ≤ 10 μM) identified in the HTS campaign.

Scheme 1. Synthesis of the Tetrahydroisoquinoline Scaffold and Its Analogues 1b–26b

(a) (i) Two equivalents of tetrahydroisoquinoline, THF, reflux, 12 h, 80–85%; (ii) aqueous NaOH; (iii) 10% HCl. (b) Anilines, HBTU, DIPEA, DMF, room temperature, 12 h, 55–75%.