Patent Watch

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.

General structure 1 and three examples of FPRL-1 receptor modulators

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.

Data table. Example 2 : 2.3 nM, Relative efficacy: 0.92. Example 3: 1 nM, Relative efficacy 0.96. Example 4: 19,315 nM, Relative efficacy: 0.45.

(Allergan [Irvine, CA]. WIPO Publication 2013062947, May2, 2013; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.

View patent information from CAplus(SM) database.

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