ARM1 (4-(4-benzylphenyl) thiazol-2-amine) is a LTB4 synthesis inhibitor [1].
Leukotriene A4 (LTA4) hydrolase/aminopeptidase is a bifunctional zinc metalloenzyme that catalyzes the synthesis of the proinflammatory mediator LTB4 from LTA4 and cleaves the chemotactic tripeptide Pro-Gly-Pro. LTB4 is a key lipid mediator in the innate immune response [1][2].
ARM1 is a LTB4 synthesis inhibitor. ARM1 is a thiazolamine that inhibits LTB4 synthesis and conversion of LTA4 to LTB4 by purified LTA4H with Ki value of 2.3 μM. 50- to 100-fold higher concentrations of ARM1 did not significantly affect hydrolysis of Pro-Gly-Pro by LTA4 hydrolase. In isolated human polymorphonuclear neutrophils (PMNs), ARM1 efficiently inhibited LTB4 synthesis with IC50 value of about 0.5 μM and complete inhibition at 5 μM. ARM1 inhibited the epoxide hydrolase activity of LTA4H without significantly affecting its ability to cleave Pro-Gly-Pro. In the crystal structure of LTA4H in complex with ARM1, ARM1 occupied the binding site for the ω-end of LTA4 [1].
References:
[1]. Stsiapanava A, Olsson U, Wan M, et al. Binding of Pro-Gly-Pro at the active site of leukotriene A4 hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor. Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):4227-32.
[2]. Haeggstrm JZ. Leukotriene A4 hydrolase/aminopeptidase, the gatekeeper of chemotactic leukotriene B4 biosynthesis. J Biol Chem. 2004 Dec 3;279(49):50639-42.
[3]. Snelgrove RJ, Jackson PL, Hardison MT, et al. A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science. 2010 Oct 1;330(6000):90-4.