1. Pyrazole Agonist of the Apelin Receptor Improves Symptoms of Metabolic Syndrome in Mice
- Author
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Shaobin Wang, Scott P. Runyon, Lucas Laudermilk, Vineetha Vasukuttan, Ravi Kumar Vyas Devambatla, Rangan Maitra, Sanju Narayanan, Rodney W. Snyder, Chunyang Jin, and Donghua Dai
- Subjects
Male ,Agonist ,medicine.drug_class ,Endogeny ,Pharmacology ,01 natural sciences ,Mice ,03 medical and health sciences ,In vivo ,Weight Loss ,Drug Discovery ,medicine ,Animals ,Humans ,Obesity ,Receptor ,030304 developmental biology ,Apelin receptor ,ADME ,Metabolic Syndrome ,Apelin Receptors ,0303 health sciences ,Chemistry ,medicine.disease ,0104 chemical sciences ,Apelin ,Mice, Inbred C57BL ,010404 medicinal & biomolecular chemistry ,Pyrazoles ,Molecular Medicine ,Metabolic syndrome - Abstract
Apelin receptor agonism improves symptoms of metabolic syndrome. However, endogenous apelin peptides have short half-lives, making their utility as potential drugs limited. Previously, we had identified a novel pyrazole-based agonist scaffold. Systematic modification of this scaffold was performed to produce compounds with improved ADME properties. Compound 13 with favorable agonist potency (cAMPi EC50 = 162 nM), human liver microsome stability (T1/2 = 62 min), and pharmacokinetic profile in rodents was identified. The compound was tested in a mouse model of diet-induced obesity (DIO) and metabolic syndrome for efficacy. Treatment with 13 led to significant weight loss, hypophagia, improved glucose utilization, reduced liver steatosis, and improvement of disease-associated biomarkers. In conclusion, a small-molecule agonist of the apelin receptor has been identified that is suitable for in vivo investigation of the apelinergic system in DIO and perhaps other diseases where this receptor has been implicated to play a role.
- Published
- 2021