Laflunimus

Laflunimus (HR325) is an immunosuppressive agent and an analogue of the Leflunomide-active metabolite A77 1726. Laflunimus is an orally active inhibitor of dihydroorotate dehydrogenase (DHODH). Laflunimus suppresses immunoglobulin (Ig) secretion, with IC50 values of 2.5 and 2 µM for IgM and IgG, respectively. Laflunimus also is a prostaglandin endoperoxide H synthase (PGHS) -1 and -2 inhibitor[1][2].

Signaling Pathways >> Cell Cycle/DNA Damage >> DNA/RNA Synthesis

Signaling Pathways >> GPCR/G Protein >> Prostaglandin Receptor

Research Areas >> Inflammation/Immunology

Ig secretion from mouse splenocytes was induced by lipopolysaccharide (LPS) for 5 days. Laflunimus inhibited the secretion of IgM and IgG with IC50 values of 2.5 and 2 µM , respectively. Adding Uridine (50 µ M) increased these values to 70 and 60 µ M, respectively. Laflunimus inhibits LPS-induced kappa light-chain cell surface expression on 70Z/3 cells, a property also reversed by uridine[1]. Laflunimus (HR325) is more potent than A77 1726 as an inhibitor of PGHS in guinea pig polymorphonuclear leukocytes (IC50= 415 and 4400 nM, respectively) and on isolated ovine PGHS-1 (IC50=64 and 742 µM) and PGHS-2 (IC50=100 and 2766 µM)[2].

HR325 (50 mg/kg; p.o.; days 14-18 after being injected with SRBC) inhibits the secondary anti-sheep red blood cell (SRBC) antibody response with ID50 values of 38 mg/kg[1]. Animal Model: Male CD-1 mice (20-24 g)[1] Dosage: 50 mg/kg Administration: Oral; days 14-18 after being injected with SRBC Result: The level of circulating anti-SRBC IgG in this model was inhibited dose relatedly by orally administered HR325.

[1]. Thomson TA, et al. In vitro and in Vivo inhibition of immunoglobulin secretion by the immunosuppressive compound HR325 is reversed by exogenous uridine. Scand J Immunol. 2002 Jul;56(1):35-42.

[2]. Curnock AP, et al. Potencies of leflunomide and HR325 as inhibitors of prostaglandin endoperoxide H synthase-1 and -2: comparison with nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Ther. 1997 Jul;282(1):339-47.