Tetrahydroimidazo[4,5-c]pyridine-Based Inhibitors of Porphyromonas gingivalis Glutaminyl Cyclase

Abstract

Periodontitis is a severe yet underestimated oral disease. Since it is linked to several systemic diseases, such as diabetes, artheriosclerosis, and even Alzheimer’s disease, growing interest in treating periodontitis has emerged recently. The major cause of periodontitis is a shift in the oral microbiome. A keystone pathogen that is associated with this shift is Porphyromonas gingivalis. Hence, targeting P. gingivalis came into focus of drug discovery for the development of novel antiinfective compounds. Among others, glutaminyl cyclases (QCs) of oral pathogens might be promising drug targets. Here, we report the discovery and structure–activity relationship of a novel class of P. gingivalis QC inhibitors according to a tetrahydroimidazo[4,5-c]pyridine scaffold. Some compounds exhibited activity in the lower nanomolar range and thus were further characterized with regard to their selectivity and toxicity.

Development and evolution of human glutaminyl cyclase inhibitors (QCIs): an alternative promising approach for disease-modifying treatment of Alzheimer's disease

“…Therefore, inhibitors designed for bacterial QCs may also bind to and suppress hQC activity. For example, PgQC inhibitors 22-24 (Table 2B) designed for the treatment of periodontitis are almost equally potent in suppressing hQC activity in vitro (Lamers et al, 2021;Ramsbeck et al, 2021). Meanwhile, another inhibitor 25 with imidazo[4,5-b]pyridin scaffold exhibited a significantly improved selectivity (>12) over PgQC (Taudte et al, 2021).…”

“…Although the activity of 21 was significantly decreased compared with the lead compound PBD150 due to the loss of the classic urea motif, the acquisition of SAR and the simple synthesis route of DPCIs still made it an ideal lead scaffold for further structural optimization. (A) QCIs designed for improving BBB permeability 21 (Li et al, 2017) (B) QCIs designed for non-hsQC with potent hsQC inhibitory activity 22-24 (Ramsbeck et al, 2021); 25 (Taudte et al, 2021) 26 (Park et al, 2022) .…”