Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1-7 analogues
2014 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, ACS medicinal chemistry letters, ISSN 1948-5875, Vol. 5, no 12, 1272-1277 p.Article in journal (Refereed) Published
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.
IdentifiersURN: urn:nbn:se:uu:diva-240408DOI: 10.1021/ml5002954ISI: 000346322500003PubMedID: 25516784OAI: oai:DiVA.org:uu-240408DiVA: diva2:776459