Design of pyrido[2,3-d]pyrimidin-7-one inhibitors of receptor interacting protein kinase-2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling

Journal article

Receptor interacting protein kinase-2 (RIPK2) is an enzyme involved in the transduction of pro-inflammatory nucleotide-binding oligomerization domain (NOD) cell signaling, a pathway implicated in numerous chronic inflammatory conditions. Herein, a pyrido[2,3-d]pyrimidin-7-one based class of RIPK2 kinase and NOD2 cell signaling inhibitors is described. For example, 33 (e.g. UH15–15) inhibited RIPK2 kinase (IC50 = 8 ± 4 nM) and displayed > 300-fold selectivity versus structurally related activin receptor-like kinase 2 (ALK2). This molecule blocked NOD2-dependent HEKBlue NF-κB activation (IC50 = 20 ± 5 nM) and CXCL8 production (at concentrations > 10 nM). Molecular docking suggests that engagement of Ser25 in the glycine-rich loop may provide increased selectivity versus ALK2 and optimal occupancy of the region between the gatekeeper and the αC-helix may contribute to potent NOD2 cell signaling inhibition. Finally, this compound also demonstrated favorable in vitro ADME and pharmacokinetic properties (e.g. Cmax = 5.7 μM, Tmax = 15 min, t1/2 = 3.4 h and Cl = 45 mL/min/kg following single 10 mg/kg intraperitoneal administration) further supporting the use of pyrido[2,3-d]pyrimidin-7-ones as a new structure class of RIPK2 kinase and NOD cell signaling inhibitors.

Authors: Nikhar, S; Siokas, I; Schlicher, L; Lee, S; Gyrd-Hansen, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: European Journal of Medicinal Chemistry
• Volume: 215
• Issue: 5 April 2021
• Article number: 113252
• Publication date: 2021-02-03
• Acceptance date: 2021-01-29
• DOI: 10.1016/j.ejmech.2021.113252
• EISSN: 1768-3254
• ISSN: 0223-5234
• Language: English
• Keywords: nucleotide-binding oligomerization domain; FFR; kinase; pyrido[2,3-d]pyrimidin-7-one; inhibitor; RIPK2; NOD; receptor-interacting protein kinase 2