July 15, 2013
These FPRL-1 receptor modulators may help treat inflammation. R. L. Beard and co-inventors disclose amide derivatives of N-urea-substituted amino acids represented by structure 1 that modulate the N-formyl peptide receptor–like-1 (FPRL-1) receptor. These compounds may potentially treat disorders such as inflammation that are associated with FPRL-1 receptor modulation.
The FPRL-1 receptor is a G protein–coupled receptor that is expressed on inflammatory cells such as monocytes, neutrophils, and T cells. It plays a critical role in leukocyte trafficking during inflammation. FPRL-1 is a promiscuous receptor: It responds to many exogenous and endogenous ligands. It transduces anti-inflammatory effects of lipoxin A4 (LXA4) and annexin A1 and can mediate the pro-inflammatory signaling cascade of peptides such as serum amyloid A.
LXA4 and annexin A1 activate FPRL-1, which inhibits polymorphonuclear neutrophil and eosinophil migration. FPRL-1 also stimulates monocyte migration to clear apoptotic cells from the inflammation site in a nonphlogistic manner. FPRL-1 inhibits natural killer cell cytotoxicity and promotes the activation of T cells, which contributes to down-regulation of tissue-damaging inflammatory signals.
The interaction of FPRL-1 with LXA4 was beneficial in several experimental inflammation models. FPRL-1 modulation is thus a therapeutic target for treating diseases that cause excessive inflammatory responses.
The inventors synthesized 91 compounds with structure 1. Three representative examples are shown in the figure. The compounds were tested for FPRL-1 activity at concentrations ranging from 0.61 to 10,000 nM. The table shows the results for the three examples, expressed as EC50 and relative efficacy.