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Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1-7 analogues
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2014 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, ACS medicinal chemistry letters, ISSN 1948-5875, Vol. 5, no 12, 1272-1277 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2014. Vol. 5, no 12, 1272-1277 p.
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Pharmaceutical Sciences
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URN: urn:nbn:se:uu:diva-240408DOI: 10.1021/ml5002954ISI: 000346322500003PubMedID: 25516784OAI: oai:DiVA.org:uu-240408DiVA: diva2:776459
Available from: 2015-01-07 Created: 2015-01-07 Last updated: 2017-12-05Bibliographically approved

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Fransson, RebeccaCarlsson-Jonsson, AnnaSvensson, RichardArtursson, PerHallberg, MathiasSandström, Anja

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