148983-03-3Relevant articles and documents
Metabolically stable apelin-analogues, incorporating cyclohexylalanine and homoarginine, as potent apelin receptor activators
Fernandez, Kleinberg X.,Fischer, Conrad,Gheblawi, Mahmoud,Gottschalk, Samantha,Iturrioz, Xavier,Oudit, Gavin Y.,Vederas, John C.,Vu, Jennie,Wang, Wang,Llorens-Cortés, Catherine
, p. 1402 - 1413 (2021/11/11)
High blood pressure and consequential cardiovascular diseases are among the top causes of death worldwide. The apelinergic (APJ) system has emerged as a promising target for the treatment of cardiovascular issues, especially prevention of ischemia reperfusion (IR) injury after a heart attack or stroke. However, rapid degradation of the endogenous apelin peptides in vivo limits their use as therapeutic agents. Here, we study the effects of simple homologue substitutions, i.e. incorporation of non-canonical amino acids l-cyclohexylalanine (l-Cha) and l-homoarginine (l-hArg), on the proteolytic stability of pyr-1-apelin-13 and apelin-17 analogues. The modified 13-mers display up to 40 times longer plasma half-life than native apelin-13 and in preliminary in vivo assay show moderate blood pressure-lowering effects. The corresponding apelin-17 analogues show pronounced blood pressure-lowering effects and up to a 340-fold increase in plasma half-life compared to the native apelin-17 isoforms, suggesting their potential use in the design of metabolically stable apelin analogues to prevent IR injury. This journal is
Discovery of Novel Nonpeptidic PAR2 Ligands
Gmeiner, Peter,Hübner, Harald,Kaindl, Jonas,Kl?sel, Ilona,Schmidt, Maximilian F.,Weikert, Dorothee
, p. 1316 - 1323 (2020/07/04)
Proteinase-activated receptor 2 (PAR2) is a class A G protein-coupled receptor whose activation has been associated with inflammatory diseases and cancer, thus representing a valuable therapeutic target. Pathophysiological roles of PAR2 are often characterized using peptidic PAR2 agonists. Peptidic ligands are frequently unstable in vivo and show poor bioavailability, and only a few approaches toward drug-like nonpeptidic PAR2 ligands have been described. The herein-described ligand 5a (IK187) is a nonpeptidic PAR2 agonist with submicromolar potency in a functional assay reflecting G protein activation. The ligand also showed substantial β-arrestin recruitment. The development of the compound was guided by the crystal structure of PAR2, when the C-terminal end of peptidic agonists was replaced by a small molecule based on a disubstituted phenylene scaffold. IK187 shows preferable metabolic stability and may serve as a lead compound for the development of nonpeptidic drugs addressing PAR2.
Influence of lipophilicity on the biological activity of cyclic pseudopeptide NK-2 receptor antagonists
Quartara,Fabbri,Ricci,Patacchini,Pestellini,Maggi,Pavone,Giachetti,Arcamone
, p. 3630 - 3638 (2007/10/02)
A series of cyclic pseudopeptides of the formula cyclo(LeuΨ[CH2NH]Xaa- Gln-Trp-Phe-βAla), where Xaa represents the residue of an α-amino acid, has been synthesized in order to establish the role of the Xaa side chain for tachykinin NK-2 recepto