Nonpeptidic Ligands for Peptide‐Activated G Protein‐Coupled Receptors

Abstract

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Pathway‐selective antagonism of proteinase activated receptor 2

“…Protein and peptide-activated GPCRs are embedded in the plasma membrane of cells and are pivotal mediators in disease (Tyndall et al, 2005;Blakeney et al, 2007). About 30% of all pharmaceutical agents activate (agonist) or inhibit (antagonist) GPCRs.…”

“…About 30% of all pharmaceutical agents activate (agonist) or inhibit (antagonist) GPCRs. Many GPCR ligands were discovered by screening chemical libraries for GPCR binding, followed by optimizing for higher affinity, selectivity and functional potency in one or two in vitro assays (Klabunde and Hessler, 2002;Blakeney et al, 2007). Compounds assigned as agonists…”

15 Kallikrein-related Peptidases (KLKs), Proteinase-mediated Signaling and Proteinase-activated Receptors (PARs)

“…A potent PAR1 antagonist ER129614-06, which has the advantage of being orally bioavailable, efficiently blocks platelet aggregation and is antithrombotic in a guinea pig model (Kawahara et al, 2004), but has yet to be evaluated in humans. Interestingly, two other recently reported compounds, F16357 and F16618, are less potent PAR1 antagonists (IC 50 of 10 μM against receptor activation by the peptide SFLLR-NH 2 in vitro), but have potent antithrombotic effects in a rat shunt model in vivo, very possibly because of off-target effects against non-PAR GPCRs (Blakeney et al, 2007;Perez et al, 2009). An additional potent and selective PAR1 antagonist and anti-platelet agent developed by the Schering group, SCH530348, although showing initial promise in trials for coronary artery disease (Chackalamannil et al, 2008), was recently withdrawn from clinical development (Gurbel et al, 2011).…”

Limiting Assumptions in the Design of Peptidomimetics

“…Reverse turns predominate on the surface of proteins and project their amino-acid sidechains in particular orientations, often used as recognition motifs; a good example are Gprotein coupled receptors (GPCRs; Tyndall et al, 2005b]. Extensive research has led to nonpeptidic compounds binding to the peptide recognition sites as peptidomimetics [Blakeney et al, 2007]. Extended conformations seen in b-sheets are common recognition motifs for proteolytic enzymes [Tyndall and Fairlie, 1999;Tyndall et al, 2005a;Madala et al, 2010], for example, HIV-1 protease.…”