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  • The pharmacokinetics of was obtained in

    2021-10-16

    The pharmacokinetics of was obtained in mouse, rat and dog to determine if it had a suitable profile to investigate the effects of the GPR120 mechanism (). had an adequate half-life, low clearance in all 3 species, and high blood levels and bioavailability. The low volume of distribution (V) indicates that mainly resides in the plasma compartment, most likely due to its high plasma protein binding. Although not ideal, this profile was thought to be sufficient for studies in rodents. An anesthetized guinea pig study was performed to gauge the cardiovascular safety of . There was no effect on the PQ, QRS, QT or QTcB intervals, heart rate, body temperature or ECG morphology, however did significantly decrease mean arterial blood pressure by 10% relative to vehicle at 22.4 mg/kg (C 105,000 ng/mL), the highest concentration tested. Next, MK 571 mg was evaluated in an oral glucose tolerance test (oGTT) in diet-induced obese (DIO) mice to assess the consequences of GPR120 agonism in an acute model of type 2 diabetes (). was dosed orally at doses from 0.1 to 3.0 mg/kg 30 min (time-30) prior to the oral glucose administration (time 0), and glucose levels were measured from 30 min pre-glucose to 90 min post-glucose. lowered glucose in a dose-dependent manner, significantly lowering glucose at 1 and 3 mg/kg. The 3 mg/kg dose lowered glucose to an extent similar to saxagliptin, a DPP-4 inhibitor positive control, at 1 mg/kg. To confirm that the glucose-lowering effect of compound was MK 571 mg indeed on target, an intra-peritoneal GTT was performed at 10 mg/kg in GPR120 knockout mice and in wild-type mice (). While lowered glucose to a significant extent in the wild-type mice, it did not show any appreciable difference in acute glucose-lowering in the GPR120 KO mice compared to vehicle thus confirming that the glucose-lowering effect is due to agonism of GPR120, and not an off-target effect from GPR40, for example. Next, compound was assessed in a 2-week DIO mouse model of type 2 diabetes to determine its effects on metabolic parameters after repeat dosing (). Compound was delivered at 10 mg/kg QD, 10 mg/kg BID, and 30 mg/kg QD along with a positive control, rosiglitazone at 3 mg/kg QD, for 15 days. Both rosiglitazone and the 30 mg/kg dose of significantly reduced both fasting glucose and insulin compared to vehicle. at 30 mg/kg also significantly lowered body weight 4.6% relative to vehicle in this study. These effects on both fasting glucose and insulin at 30 mg/kg QD were confirmed in a second 15-day DIO assay conducted in the same manner, and give credence to the insulin-sensitizing effects of GPR120 agonism. In summary, we have discovered a new class of heterocyclic GPR120 agonists with good potency and acceptable pharmacokinetic properties that show positive effects in both acute and chronic rodent models of type 2 diabetes. We hope to report on further development of this series in the future. Acknowledgements
    Introduction The overwhelming prevalence of diet-induced obesity (DIO) and insulin resistance (IR) is strongly associated with the increased morbidity and mortality related to metabolic syndrome [1]. This is of great concern in the United States of America where the obesity rates are rising and is currently approximately 39.8%, with over 93.3 million adults affected, and there is still a lack of understanding of its etiology [2]. Redox regulation is key for systemic metabolic homeostasis. Furthermore, redox stress is an important mediator of metabolic changes seen in obesity and its comorbidities which comprise the metabolic syndrome [3]. Oxygen and nitrogen-derived free radicals alter glucose and lipid homeostasis in key metabolic tissues such as adipose, liver, brain, and skeletal muscle. During conditions of high redox stress, the body naturally attempts to compensate by increasing the production of endogenous antioxidants (including superoxide dismutase-SOD, catalase etc.) to counteract the excess free radicals that could damage signaling pathways necessary for energy production. It is believed that an increased level of reactive oxygen species (ROS) plays a key role in IR, since human and rodent models of IR are typically characterized by an imbalance in ROS compared to antioxidants/reducing agents [4,5]. However, recent studies have also shown the importance of maintaining adequate ROS production for intracellular signaling [6]. Furthermore, the concept of reductive stress, an imbalance in the oxidative state where the ratio of oxidized to reduced molecules is too low [[7], [8], [9]], is also shown to be associated with an altered metabolic state such as hyperglycemia [10] or IR [11]. Therefore, a balance between free radicals and antioxidants is key in maintenance of tissue function and systemic metabolic homeostasis.