title: Design and synthesis of tryptophan containing dipeptide derivatives as formyl peptide receptor 1 antagonist.
abstract: Our previous studies identified an Fmoc-(S,R)-tryptophan-containing dipeptide derivative, 1, which selectively inhibited neutrophil elastase release induced by formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) in human neutrophils. In an attempt to improve pharmacological activity, a series of tryptophan-containing dipeptides were synthesized and their pharmacological activities were investigated in human neutrophils. Of these, five compounds 3, 6, 19a, 24a, and 24b exhibited potent and dual inhibitory effects on FMLP-induced superoxide anion (O2˙(-)) generation and neutrophil elastase release in neutrophils with IC50 values of 0.23/0.60, 1.88/2.47, 1.87/3.60, 0.12/0.37, and 1.32/1.03 μM, respectively. Further studies indicated that inhibition of superoxide production in human neutrophils by these dipeptides was associated with the selective inhibition of formyl peptide receptor 1 (FPR1). Furthermore, the results of structure-activity relationship studies concluded that the fragment N-benzoyl-Trp-Phe-OMe (3) was most suitable as a core structure for interaction with FPR1, and may be approved as a lead for the development of new drugs in the treatment of neutrophilic inflammatory diseases. As some of the synthesized compounds exhibited separable conformational isomers, and showed diverse bioactivities, the conformation analysis of these compounds is also discussed herein.
authors: Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
authors: Tsong-Long
authors: TL
authors: Hwang
authors: Chih-Hao
authors: CH
authors: Hung
authors: Ching-Yun
authors: CY
authors: Hsu
authors: Yin-Ting
authors: YT
authors: Huang
authors: Yu-Chi
authors: YC
authors: Tsai
authors: Pei-Wen
authors: PW
authors: Hsieh
mesh_terms: D000328:Adult; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D004151:Dipeptides; C469986:FPR1 protein, human; D044042:Receptors, Formyl Peptide; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D014364:Tryptophan; D010196:Pancreatic Elastase