Pyrazole Agonist of the Apelin Receptor Improves Symptoms of Metabolic Syndrome in Mice

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 (T 1/2 = 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.

Scaffold Hopping Strategy to Identify Prostanoid EP4 Receptor Antagonists for Cancer Immunotherapy

“…On the basis of their favorable in vitro biological activities, compounds with better activity and selectivity were selected to further explore their drug-like properties, and the corresponding compounds were submitted for preliminary absorption, distribution, metabolism, excretion (ADME) tests . As depicted in Table , compounds 17 and 18 showed poor stability in HLMs, with half-lives of only 6.3 and 14 min, as well as only 12.2 and 5.0% of the compounds remained, respectively, after 60 min of incubation.…”

The Role of Apelin–APJ System in Diabetes and Obesity

“…In addition, these mice also showed increased abdominal and epididymal fat without a difference in body weight ( 105 ). The apelin -/- mice were more glucose and insulin intolerant when they were fed with a high-fat diet and high-sucrose drinking water ( 121 ). Stable apelin-13 peptide analogues have shown promising short-term antidiabetic effects in mice with diet-induced obesity and diabetes ( 122 ).…”

Transition Metal‐ and Oxidant‐Free Regioselective Synthesis of 3,4,5‐Trisubstituted Pyrazoles by Means of [3+2] Cycloaddition Reactions

“…[18][19][20] Apart from these, they have also used as bifunctional ligands in transition metal-catalyzed reactions [21] and as artificial receptors. [22] Over the past decade, various methodologies have been developed for the synthesis of pyrazoles. For example, transition metal catalyzed cross-coupling reactions, [23] [3 + 2] cycloaddition reactions of Bestmann-Ohira reagent and Seyferth-Gilbert reagent with olefinic derivatives, [24] [4 + 1] annulation using hydrazones [25] and Knorr condensation of hydrazines with 1,3-dicarbonyl compounds.…”