Identification of pyrazolo-pyrimidinones as GHS-R1a antagonists and inverse agonists for the treatment of obesityElectronic supplementary information (ESI) available: Synthetic details for the preparation of compounds and protocols for biological and physicochemical measurements. See DOI: 10.1039/c2md20340e

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. Scaffold hop and LLE optimisation led to novel CNS penetrant growth hormone secretagogue receptor type 1a (GHS-R1a) antagonists and inverse agonists.