Peroxisome proliferator-activated receptor gamma (PPARγ) is a dominant regulator of adipose cell differentiation and development, structurally belonging to the nuclear hormone receptor (NHR) superfamily. It is also well known as the target protein for the currently marketed thiazolidinedione (TZD) class of anti-diabetic drugs such as rosiglitazone (Avandia, GSK) and pioglitazone (Actos, Takeda). From a clinical perspective, these TZD drugs act as the full agonists of PPARγ and are highly effective oral medications for type 2 diabetes mellitus (T2DM). However, many clinical studies have showed that administration of these TZD drugs is associated with many undesirable side effects such as obesity, fluid retention, weight gain, cardiac hypertrophy, hepatotoxicity and loss of bone mineral density. Undoubtedly, there is an urgent need to discover new, safe and highly efficient PPARγ agonists with improved therapeutic profiles.

Inspired by these, researchers from H Eric Xu group designed and synthesized a series of novel selectively PPARγ modulators that called VSP series (Chinese Patent, application number: 201410025241.1 and 201410289010.1). Structure modifications to discover that compound VSP-51 had a potent binder toward PPARγ with desired properties. For example, in vitro, it was a partial agonist of PPARγ and has a potent binding affinity for PPARγ without stimulating adipocyte differentiation and the expression of adipogenesis-related genes. In vivo, it showed powerful glucose-lowering effects but with reduced adverse effects. Crystal structure analysis revealed that VSP-51 has a unique mode of binding to PPARγ compared to TZDs, which provides the molecular basis for the discrimination of VSP-51 from TZDs.

Notably, by the analysis of VSP-51 complex crystal structure, we also found that there is a potent hydrophobic pocket near to C2-position of indole nucleus, suggesting that such region can be exploited for future new pharmacological agents targeting PPARγ by using VSP-51 as the unique template. Based on this, researchers led by Prof. H Eric Xu and Dr. Wei Yi developed for the first time Rh(III)-catalyzed regioselective direct C2-H activation of indoles to give access to a series of 2-functionalized indoles (Chem. Commun., 2014, 50, 6438-6486; Adv. Synth. Catal., 2014, 356, 137-143.). The biological evaluation showed that these synthesized compounds can serve as promising candidates for the treatment of T2DM and as lead compounds for the development of new pharmacophores selectively targeting PPARγ (Org. Biomol. Chem., 2014, 6831-6836, selected as Inside front cover).

The above works were supported by the Chinese Postdoctoral Science Foundation (2012M511158 and 2013T60477), the Jay and Betty Van Andel Foundation, and Amway (China).

The link to related articles:

For Chem. Commun: http://pubs.rsc.org/en/content/articlelanding/2014/cc/c4cc01593b

For Adv. Synth. Catal: http://onlinelibrary.wiley.com/doi/10.1002/adsc.201300700

For Org. Biomol. Chem: http://pubs.rsc.org/en/content/articlelanding/2014/ob/c4ob00637b

For Inside front cover: http://pubs.rsc.org/en/content/articlepdf/2014/ob/c4ob90121e?page=search

Structure-based synthesis of C2-functionalized VSP-51 derivatives as novel selective PPARγ modulators
(Image by SIMM)

(Source: Professor H Eric.Xu’s group)