title: Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1-7 analogues.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Uppsala University , SE-751 23 Uppsala, Sweden.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Fransson
authors.affiliation: CNSP iMed Södertälje , AstraZeneca Research & Development, Innovative Medicines, SE-151 85 Södertälje, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Nordvall
authors.affiliation: CNSP iMed Södertälje , AstraZeneca Research & Development, Innovative Medicines, SE-151 85 Södertälje, Sweden ; Department of Pharmaceutical Biosciences, Uppsala University , SE-751 24 Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Bylund
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University , SE-751 24 Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Carlsson-Jonsson
authors.affiliation: Department of Pharmacy, Uppsala University , SE-751 23 Uppsala, Sweden.
authors.forename: Jadel M
authors.initials: JM
authors.lastname: Kratz
authors.affiliation: Department of Pharmacy, Uppsala University , SE-751 23 Uppsala, Sweden ; The Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium Sweden, Uppsala University , SE-751 23 Uppsala, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Svensson
authors.affiliation: Department of Pharmacy, Uppsala University , SE-751 23 Uppsala, Sweden ; The Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium Sweden, Uppsala University , SE-751 23 Uppsala, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University , SE-751 24 Uppsala, Sweden.
authors.forename: Mathias
authors.initials: M
authors.lastname: Hallberg
authors.affiliation: Department of Medicinal Chemistry, Uppsala University , SE-751 23 Uppsala, Sweden.
authors.forename: Anja
authors.initials: A
authors.lastname: Sandström
keywords: Caco-2 cells; SP1−7; Substance P 1−7; bioisostere; neuropathic pain