Constrained H-Phe-Phe-NH2 Analogues with High Affinity to the Substance P 1鈥? Binding Site and with Improved Metabolic Stability and Cell Permeability

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• 作者：Rebecca Fransson ; Christian Sk枚ld ; Jadel M. Kratz ; Richard Svensson ; Per Artursson ; Fred Nyberg ; Mathias Hallberg ; Anja Sandstr枚m
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 27, 2013
• 年：2013
• 卷：56
• 期：12
• 页码：4953-4965
• 全文大小：398K
• 年卷期：v.56,no.12(June 27, 2013)
• ISSN：1520-4804

文摘

We recently reported the discovery of H-Phe-Phe-NH₂ as a small and high affinity ligand for the substance P 1鈥? (SP_1鈥?, H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) specific binding site and its intriguing ability to reduce neuropathic pain. With the overall aim to develop stable and orally bioavailable SP_1鈥? mimetics, the dipeptide was chosen as a lead compound. Herein the structure鈥揳ctivity relationship (SAR) of a set of modified H-Phe-Phe-NH₂ analogues is presented together with their potential active uptake by PEPT1 transporter, intestinal permeability, and metabolic stability. Local constraints via peptide backbone methylation or preparation of cyclized analogues based on pyrrolidine were evaluated and were shown to significantly improve the in vitro pharmacokinetic properties. The SAR was rationalized by deriving a plausible binding pose for the high affinity ligands. Rigidification using a 3-phenylpyrrolidine moiety in the C-terminal of H-Phe-Phe-NH₂ resulted in high affinity and improved intrinsic clearance and intestinal epithelial permeability.