Scientists in the UK and Sweden have identified compounds that work against a ligand (ghrelin) that’s part of a growth hormone that’s thought to increase the amount of food we eat. The compounds could be used to prevent obesity and diabetes.
Ghrelin, a 28 amino acid acylated peptide hormone, is the endogenous ligand of growth hormone secretagogue receptor type 1a (GHS-R1a), and is thought to control food intake. Acylated ghrelin is released from mucosal cells in response to hunger cues, resulting in a peak of plasma ghrelin levels before meals. It has also been shown that ghrelin infusion in both rodents and humans increases appetite and food intake. Therefore, peripheral and central nervous system (CNS) penetrant ghrelin receptor antagonists could be a potential cure for obesity and diabetes.
In this work, the team identified a tool compound within a pyrazolo-pyrimidinone based series of GHS-R1a antagonists that had good overall properties and sufficient oral plasma and CNS exposure to demonstrate reduced food intake in mice through a mechanism involving GHS-R1a.
Identification of pyrazolo-pyrimidinones as GHS-R1a antagonists and inverse agonists for the treatment of obesity
William McCoull, Peter Barton, Anders Broo, Alastair Brown, David Clarke, Gareth Coope, Rob D M Davies, Alastair Dossetter, Elizabeth Kelly, Laurent Knerr, Philip Macfaul, Jane Holmes, Nathaniel Martin, Jane E Moore, David Morgan, Claire Newton, Krister Osterlund, Graeme Robb, Eleanor Rosevere, Nidhal Selmi, Stephen Stokes, Tor Svensson, Victoria Ullah and Emma Williams
Med. Chem. Commun.
DOI: 10.1039/C2MD20340E
