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7103401 
Journal Article 
Exploration and Pharmacokinetic Profiling of Phenylalanine Based Carbamates as Novel Substance P 1-7 Analogues 
Fransson, R; Nordvall, G; Bylund, J; Carlsson-Jonsson, A; Kratz, JM; Svensson, R; Artursson, Per; Hallberg, M; Sandstrom, A; , 
2014 
Yes 
ACS Medicinal Chemistry Letters
ISSN: 1948-5875 
AMER CHEMICAL SOC 
WASHINGTON 
1272-1277 
25516784 
WOS:000346322500003 
The bioactive metabolite of Substance P, the heptapeptide SP1-7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compounds targeting the SP1-7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1-7 peptidomimetics we have previously reported on the discovery of H-Phe-Phe-NH2 as a high affinity lead compound. Unfortunately, the pharmacophore of this compound was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1-7 analogues with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compound. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide.