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Issue 2, 2013
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Identification of pyrazolo-pyrimidinones as GHS-R1a antagonists and inverse agonists for the treatment of obesity

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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.

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

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Publication details

The article was received on 09 Nov 2012, accepted on 15 Dec 2012 and first published on 20 Dec 2012


Article type: Concise Article
DOI: 10.1039/C2MD20340E
Citation: Med. Chem. Commun., 2013,4, 456-462
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    Identification of pyrazolo-pyrimidinones as GHS-R1a antagonists and inverse agonists for the treatment of obesity

    W. McCoull, P. Barton, A. Broo, A. J. H. Brown, D. S. Clarke, G. Coope, R. D. M. Davies, A. G. Dossetter, E. E. Kelly, L. Knerr, P. MacFaul, J. L. Holmes, N. Martin, J. E. Moore, D. Morgan, C. Newton, K. Österlund, G. R. Robb, E. Rosevere, N. Selmi, S. Stokes, T. S. Svensson, V. B. K. Ullah and E. J. Williams, Med. Chem. Commun., 2013, 4, 456
    DOI: 10.1039/C2MD20340E

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