BIRT 377

BIRT 377 is a negative allosteric modulator (NAM) of lymphocyte function-associated antigen-1 (LFA-1).¹ It binds to LFA-1 at a site distal to residues involved in intercellular adhesion molecule interactions and induces a conformational change to its inactive state.² BIRT 377 selectively inhibits the interaction of LFA-1 to intercellular adhesion molecule-1 (ICAM-1) over the interaction between ITGAM/CD11b, also known as Mac-1, and ICAM-1 in cell-free assays at 225 µM.¹ It inhibits LFA-1-mediated binding of SKW-3 cells to ICAM-1 (IC₅₀ = 2.6 µM) and reduces plasma IL-2 levels increased by staphylococcal enterotoxin B (SEB) in mice when administered at doses of 25 and 50 mg/kg. Intrathecal administration of BIRT 377 (500 ng/animal) reduces allodynia in prenatal alcohol exposed (PAE) rats in a model of sciatic neuropathy induced by a minor chronic constriction injury.³

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1. Kelly, T.A., Jeanfavre, D.D., McNeil, D.W., et al. Cutting edge: A small molecule antagonist of LFA-1-mediated cell adhesion. J. Immunol. 163(10), 5173-5177 (1999).

2. Last-Barney, K., Davidson, W., Cardozo, M., et al. Binding site elucidation of hydantoin-based antagonists of LFA-1 using multidisciplinary technologies: Evidence for the allosteric inhibition of a protein--protein interaction. J. Am. Chem. Soc. 123(24), 5643-5650 (2001).

3. Sanchez, J.J., Sanchez, J.E., Noor, S., et al. Targeting the β₂-integrin LFA-1, reduces adverse neuroimmune actions in neuropathic susceptibility caused by prenatal alcohol exposure. Acta Neuropathol. Commun. 7(1), 54 (2019).