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While stimulation of formyl peptide receptors (FPRs) on the surface of human neutrophils induces several immune responses, under conditions of continuous activation of the receptor by agonists such as formyl-Met-Leu-Phe-OH (fMLP), neutrophil-dependent tissue damage ensues. Thus, FPR antagonists could be anticipated as drugs for FPR-related disease. In this study, Boc-Phe-D-Leu-Phe-D-Leu-Phe-OH (Boc-FlFlF), one of several FPR subtype selective antagonists, was chosen and the positions at the Phe residues were optimized. We found that substitution with unnatural amino acids resulted in an improvement of two orders of magnitude. The most potent antagonist indicated FPR subtype selectivity at 1 μM. In addition to finding a potent antagonist, the structure-activity trends observed in this study should be valuable in designing a new type of FPR subtype selective antagonist. Copyright © 2014 Elsevier Ltd. All rights reserved.


Ryo Hayashi, Toshiki Kitajima, Hikaru Mizuguchi, Miki Fujimoto, Aya Yamaguchi, Shuichiro Koga, Yuya Koga, Satoshi Osada, Hiroaki Kodama. Development of potent antagonists for formyl peptide receptor 1 based on Boc-Phe-D-Leu-Phe-D-Leu-Phe-OH. Bioorganic & medicinal chemistry. 2014 Aug 1;22(15):3824-8

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PMID: 25035262

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