Identification of pyrazolo-pyrimidinones as GHS-R1a antagonists and inverse agonists for the treatment of obesity

McCoull, William; Barton, Peter; Broo, Anders; Brown, Alastair J. H.; Clarke, David S.; Coope, Gareth; Davies, Robert D. M.; Dossetter, Alexander G.; Kelly, Elizabeth E.; Knerr, Laurent; MacFaul, Philip; Holmes, Jane L.; Martin, Nathaniel; Moore, Jane E.; Morgan, David; Newton, Claire; Österlund, Krister; Robb, Graeme R.; Rosevere, Eleanor; Selmi, Nidhal; Stokes, Stephen; Svensson, Tor S.; Ullah, Victoria B. K.; Williams, Emma J.

Abstract

A pyrazolo-pyrimidinone based series of growth hormone secretagogue receptor type 1a (GHS-R1a) antagonists and inverse agonists were identified using a scaffold hop from known quinazolinone GHS-R1a modulators. Lipophilicity was reduced to decrease hERG activity while maintaining GHS-R1a affinity. SAR exploration of a piperidine substituent was used to identify small cyclic groups as a functional switch from partial agonists to neutral antagonists and inverse agonists. A tool compound was identified which had good overall properties and sufficient oral plasma and CNS exposure to demonstrate reduced food intake in mice through a mechanism involving GHS-R1a.

Citation

McCoull, W., Barton, P., Broo, A., Brown, A. J. H., Clarke, D. S., Coope, G., …Williams, E. J. (2013). Identification of pyrazolo-pyrimidinones as GHS-R1a antagonists and inverse agonists for the treatment of obesity. MedChemComm, 4(2), 456. https://doi.org/10.1039/c2md20340e

• Journal Article Type: Article
• Acceptance Date: Dec 15, 2012
• Online Publication Date: Dec 20, 2012
• Publication Date: 2013
• Deposit Date: Jun 12, 2023
• Journal: MedChemComm
• Print ISSN: 2040-2503
• Electronic ISSN: 2040-2511
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 4
• Issue: 2
• Pages: 456
• DOI: https://doi.org/10.1039/c2md20340e
• Keywords: Pharmaceutical Science; Biochemistry; Drug Discovery; Molecular Medicine; Pharmacology; Organic Chemistry