439571-48-9

NDT 9513727 is a competitive antagonist of the C5a receptor (C5aR; IC₅₀ = 11.6 nM for human recombinant receptors) that has inverse agonist activity in a GTPγ[³⁵S] assay. It is selective for human recombinant over rat and mouse recombinant C5aRs (IC₅₀ = >10 μM for both) but does have activity at macaque and gerbil receptors (IC₅₀s = 7.3 and 6.4 nM, respectively). NDT 9513727 inhibits degranulation in U937 cells stimulated with C5a (IC₅₀ = 7.1 nM). It also prevents neutropenia induced by human recombinant C5a in gerbils (ED₅₀ = 2.2 mg/kg) and in cynomolgus macaques when administered at doses of 5 and 25 mg/kg.

NDT 9513727 is a selective, and potent inverse agonist of the human C5aR. NDT 9513727 has been shown to effectively inhibit C5a-induced neutropenia in gerbil and cynomolgus macaque in vivo. These results suggest that NDT 9513727 is a promising candidate for the treatment of human inflammatory diseases.

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[1] NATHAN ROBERTSON. Structure of the complement C5a receptor bound to the extra-helical antagonist NDT9513727[J]. Nature, 2018, 553 7686: 111-114. DOI: 10.1038/nature25025
[2] ROBBIN M BRODBECK. 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]. Journal of Pharmacology and Experimental Therapeutics, 2008, 327 3: 898-909. DOI: 10.1124/jpet.108.141572