Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a key regulator of glucose homeostasis and lipid metabolism, and an important target for the development of modern anti-diabetic drugs. However, current PPARγ-targeting anti-diabetic drugs such as classical thiazolidinediones (TZDs) are associated with undesirable side effects. To address this concern, we here describe the structure-based design, synthesis, identification and detailed in vitro and in vivo characterization of a novel, decanoic acid (DA)-based and selective PPARγ modulator (SPPARγM), VSP-77, especially (S)-VSP-77, as the potential "hit" for the development of improved and safer anti-diabetic therapeutics. We have also determined the co-crystal structure of the PPARγ ligand-binding domain (LBD) in complex with two molecules of (S)-VSP-77, which reveal a previously undisclosed allosteric binding mode. Overall, these findings not only demonstrate the therapeutic advantage of (S)-VSP-77 over current TZD drugs and representative partial agonist INT131, but also provide a rational basis for the development of future SPPARγMs as safe and highly efficacious anti-diabetic drugs.
Highlights
Type 2 diabetes mellitus (T2DM), known as non-insulindependent diabetes mellitus, accounts for >90% of all cases of diabetes
Our results demonstrate that (S)VSP-77 can serve as a promising candidate for T2DM therapy and establish a rational foundation for designing speci c drugs targeting Peroxisome proliferator-activated receptor g (PPARg) with advantages over current TZD drugs and representative partial agonist INT131
The synthesis of (R)-VSP-77 and (S)-VSP-77 (R)-VSP-77 and (S)-VSP-77 were respectively synthesized in two steps as demonstrated in Fig. 2: Firstly, a facile condensation in the presence of EDCI and DMSO to provide amides 3 and 4 in 42% and 37% yields, respectively, followed by ether hydrolysis assisted by 6 N HCl solution to afford the corresponding products (R)-VSP-77 and (S)-VSP-77 in decent yields
Summary
Type 2 diabetes mellitus (T2DM), known as non-insulindependent diabetes mellitus, accounts for >90% of all cases of diabetes This condition is characterized by high blood glucose (hyperglycemia) mainly resulting from resistance to insulin in peripheral tissue.[1] One of the most remarkable pathological features in diabetic patients is energy surplus-generated obesity. During obesity, adipose tissue might become severely dysfunction and fail to appropriately expand to store the surplus energy. These conditions lead to ectopic fat accumulation in other tissue, and progressive insulin resistance and T2DM.[2,3,4] it is crucial to target to the improvement of adipose dysfunction for regulating energy homeostasis and obesity
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