Exploration and Pharmacokinetic Profiling of Phenylalanine Based Carbamates as Novel Substance P 1鈥? Analogues

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• 作者：Rebecca Fransson ; Gunnar Nordvall ; Johan Bylund ; Anna Carlsson-Jonsson ; Jadel M. Kratz ; Richard Svensson ; Per Artursson ; Mathias Hallberg ; Anja Sandstr枚m
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：December 11, 2014
• 年：2014
• 卷：5
• 期：12
• 页码：1272-1277
• 全文大小：317K
• ISSN：1948-5875

文摘

The bioactive metabolite of Substance P, the heptapeptide SP_1鈥? (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 SP_1鈥? binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP_1鈥? 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 SP_1鈥? 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.

Keywords:

Substance P 1鈭?; bioisostere; Caco-2 cells; neuropathic pain; SP_1鈭?