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Identification, Optimization, and Pharmacology of Acylurea GHS-R1a Inverse Agonists
- Source :
- Journal of Medicinal Chemistry. 57:6128-6140
- Publication Year :
- 2014
- Publisher :
- American Chemical Society (ACS), 2014.
-
Abstract
- Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.
- Subjects :
- Models, Molecular
medicine.medical_specialty
Drug Inverse Agonism
High-throughput screening
Pharmacology
Partial agonist
Structure-Activity Relationship
chemistry.chemical_compound
Internal medicine
Drug Discovery
medicine
Humans
Urea
Inverse agonist
Structure–activity relationship
Receptors, Ghrelin
Receptor
Dose-Response Relationship, Drug
Molecular Structure
digestive, oral, and skin physiology
Endocrinology
chemistry
Molecular Medicine
Ghrelin
Penetrant (biochemical)
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 57
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....8ccfb2b1ee8726b210e078e06cca3e9c