2. Academic Validation
  3. Development of potent antagonists for formyl peptide receptor 1 based on Boc-Phe-D-Leu-Phe-D-Leu-Phe-OH

Development of potent antagonists for formyl peptide receptor 1 based on Boc-Phe-D-Leu-Phe-D-Leu-Phe-OH

  • Bioorg Med Chem. 2014 Aug 1;22(15):3824-8. doi: 10.1016/j.bmc.2014.06.048.
Ryo Hayashi 1,  Toshiki Kitajima 1,  Hikaru Mizuguchi 1,  Miki Fujimoto 1,  Aya Yamaguchi 1,  Shuichiro Koga 1,  Yuya Koga 1,  Satoshi Osada 1,  Hiroaki Kodama 2
Affiliations

Affiliations

  • 1 Department of Chemistry, Graduate School of Science and Engineering, Saga University, 1 Honjo-machi, Saga 840-8502, Japan.
  • 2 Department of Chemistry, Graduate School of Science and Engineering, Saga University, 1 Honjo-machi, Saga 840-8502, Japan. Electronic address: hiroaki@cc.saga-u.ac.jp.
PMID: 25035262 DOI: 10.1016/j.bmc.2014.06.048
Abstract

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.

Keywords

Boc-FlFlF-OH; Formyl peptide receptor; Selective antagonist.

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