Chemical Platform for the Preparation of Synthetic Orally Active Peptidomimetics with Hemoregulating Activity. (26th July 2016)

• Record Type: Journal Article
• Authors: Deigin, Vladislav; Ksenofontova, Olga; Khrushchev, Alexey; Yatskin, Oleg; Goryacheva, Alexandra; Ivanov, Vadim
• Is Part Of: ChemMedChem. Volume 11:Number 18(2016)
• Page Start: 1974
• Page End: 1977
• Publication Date: 2016-07-26
• Subjects: piperazine-2, 5-diones -- hematopoiesis -- peptidomimetics -- synthetic peptides; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201600157
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: A novel chemical platform based on branched piperazine‐2, 5‐dione derivatives (2, 5‐diketopiperazines) for creating orally available biologically active peptidomimetics has been developed. The platform includes a diketopiperazine scaffold with "built‐in" functionally active peptide fragments covalently attached via linkers. The concept was applied to two hemostimulatory drugs, the dipeptide thymogen (GluTrp) and the tripeptide stemokin (IleGluTrp). Preparation of a series of respective derivatives is described. Of the five synthesized analogues, three demonstrated high hemostimulatory activity in vivo on intact mice and on ex vivo irradiated bone marrow cells. Prospects of further development of the concept are discussed. Abstract : Robust and bioavailable ! The low stability of peptide pharmaceuticals in non‐invasive administration limits the use of these compounds in medical practice. We developed a platform based on branched piperazine‐2, 5‐diones for creating orally stable peptidomimetics. These derivatives were attached to the N or C termini of an active linear peptide, increasing their resistance against proteolytic activity. As a result, the first orally active hemostimulatory peptides have been prepared.