The complement system represents an innate immune mechanism of host defense. The complement system has three effector arms, the C3a receptor, the C5a receptor (C5aR), and the membrane attack complex. Because of its inflammatory and immune-enhancing properties, the C5aR continues to be a promising target for pharmaceutical research. NDT 9513727 is a small molecule, orally bioavailable, selective, and potent inverse agonist of the human C5aR.
C5aR is a G-protein-coupled receptor that functionally couples ligand binding to intracellular responses. In addition, C5aR activation influences cytokine and chemokine gene expression and cellular apoptosis. NDT 9513727 inhibits C5a-stimulated responses in various cell types with IC50s from 1.1 to 9.2 nM, respectively. Furthermore, NDT 9513727 exhibits an IC50 of 11.6 nM in C5a competition radioligand binding experiments. In particular, NDT 9513727 places [125I]C5a binding with an IC50 value of 11.6 nM. Although NDT 9513727 has potent activity in both gerbil and monkey (cynomolgus macaque), lung membrane preparations (6.4 and 7.3 nM, respectively), displays minimal activity in rat, mouse, and dog lung preparations (IC50 value greater than 10 uM).
NDT 9513727 is orally bioavailable, with desirable pharmacokinetics in multiple species, and it effectively inhibits C5a-induced activity in vivo and in human whole blood. Moreover, NDT 9513727 effectively inhibits C5a-induced neutropenia in gerbil and cynomolgus macaque in vivo. In addition, NDT 9513727 displays activity in a human ex vivo blood assay and in C5a-induced neutropenia gerbil and macaque models in vivo.
To summarize, NDT 9513727 is a potent, selective, and orally bioavailable small-molecule C5aR antagonist. NDT 9513727 is a promising experimental therapeutic for the treatment of human inflammatory disease.
Robbin M Brodbeck, et al. Identification and characterization of NDT 9513727 [N,N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine], a novel, orally bioavailable C5a receptor inverse agonist. J Pharmacol Exp Ther. 2008 Dec;327(3):898-909.