Selective peroxisome proliferator-activated receptor d isosteric selenium agonists as potent anti-atherogenic agents in vivo Jungwook Chin a,  , Jun Young Hong a,  , Jaehwan Lee a,  , Hoosang Hwang a , Hyunsil Ko a , Hyukjae Choi a , Dongyup Hahn a , Jaeyoung Ko a , Sang-Jip Nam a , Jungae Tak a , Jungyeob Ham b , Heonjoong Kang a,c,⇑ a Center for Marine Natural Products and Drug Discovery, School of Earth and Environmental Sciences, Seoul National University, NS-80, Seoul 151-747, Republic of Korea b Korea Institute of Science and Technology, 290 Daejeon-dong, Gangneung 210-340, Republic of Korea c Research Institute of Oceanography, SNU 151-741, Republic of Korea article info Article history: Received 18 August 2010 Revised 30 September 2010 Accepted 20 October 2010 Available online 26 October 2010 Keywords: PPARd-selective ligand Anti-atherogenic agents Intestinal polyp formation abstract We report the synthesis and in vivo activity of a novel anti-atherogenic agent, isosteric selenium PPARd-selective ligand. This ligand did not cause significant body or liver weight changes and did not have obvious adverse effects on intestinal polyp formation. Our overall results clearly demonstrate that PPARd is a viable drug candidate for targeting and treating atherosclerosis. Ó 2010 Elsevier Ltd. All rights reserved. Atherosclerosis is a disease characterized by enlarged arterial blood vessels that are induced by the dysfunction of lipid metabo- lism. This disease progresses via chronic inflammation resulting from the interaction between lesional lipoproteins and immune cells. 1 The peroxisome proliferator-activated receptors (PPARs) are transcription factors that are activated by their cognate ligands and act as master regulators in mammalian physiology and devel- opment. 2 Among the three different isoforms (PPAR-a,-c, and -d), PPARd regulates lipid homeostasis and inflammation in the human body, and the impairment of these processes can lead to athero- sclerosis. 3 Several studies have shown that the activation of PPARd promotes fatty acid catabolism and reverses cholesterol transport and represses inflammatory gene expression. These effects suggest a beneficial role of PPARd-selective agonists in the treatment of atherosclerosis. 4–6 Prior research has shown that the activation of PPARd by GW0742, 7 a PPARd agonist, increases the level of high-density lipoprotein-cholesterol (HDL-c) in DBA/1 mice. 8 Considering the atheroprotective role of HDL-c, 9 it was expected that the PPARd- selective agonist would have anti-atherogenic potential. However, recent studies have produced incompatible results regarding this prediction. In a study by Li et al., there was no obvious inhibitory anti-atherogenic effect of the PPARd agonist, independent of the PPARa and PPARc agonists, in LDLR À/À mice. 10 In contrast, Graham et al. demonstrated the anti-atherogenic potential of the PPARd agonist in LDLR À/À mice. 11 However, the inhibitory effect was only observed with a high dose regimen (60 mg/kg) or long-term treatment (16 weeks) and was associated with the adverse effect of increased liver weight. The compound was reported to have no selectivity for PPARd above 1 lM over the other isotypes. 7 Considering the serum concentration of GW0742 (21 lM at 60 mg/kg) in the study by Graham et al., the anti-atherogenic activity might have been mediated through PPARa or c activation. In this regard, it still unclear whether PPARd-selective agonists have anti-atherogenic effects. 12 We developed a series of novel selenium-containing PPARd- selective ligands to resolve this issue (Fig. 1). 13 Isosterism is a useful strategy for molecular modification and a rational approach in drug design. 14 Isosteric analogs possess an equally well-estab- lished biological potency in protein–receptor interaction. 15 Our 0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.10.103 ⇑ Corresponding author. Tel.: +82 2 880 5730; fax: +82 2 883 9289. E-mail address: hjkang@snu.ac.kr (H. Kang).   These authors contributed equally to the study. F 3 C N S Se O OH O R 2 R 3 R 1 R 1 = H, R 3 =H R 3 =H R 1 =F, R 3 = CH 3 R 3 =H R 3 =H R 1 = F, R 2 = H, R 2 = CH 3 , 2g 2h R 2 = CH 3 , R 1 = F, 1f 1g 1h R 1 = H, R 1 = H, R 2 = H, R 2 = CH 3 , R 2 = CH 3 , R 3 = CH 3 2f R 2 = CH 2 CH 3 ,R 3 =H R 1 = H, 1i R 1 = F, R 2 = CH 2 CH 3 ,R 3 =H 2i Figure 1. Structures of selenoether-containing PPARd agonists. Bioorganic & Medicinal Chemistry Letters 20 (2010) 7239–7242 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl