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Identification of pyrazolo-pyrimidinones as GHS-R1a antagonists and inverse agonists for the treatment of obesity
- Source :
- MedChemComm. 4:456
- Publication Year :
- 2013
- Publisher :
- Royal Society of Chemistry (RSC), 2013.
-
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.
- Subjects :
- Pharmacology
Food intake
biology
Chemistry
Organic Chemistry
hERG
Pharmaceutical Science
Biochemistry
Partial agonist
chemistry.chemical_compound
Pyrimidinones
Drug Discovery
Lipophilicity
biology.protein
Molecular Medicine
Inverse agonist
Piperidine
Quinazolinone
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 20402511 and 20402503
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- MedChemComm
- Accession number :
- edsair.doi...........0e338246543e6606730bbb19b24004e0