Synthesis of an Urea-substituted Selenoisobutyric Acid Isostere of the Peroxisome Proliferator-activated Receptor α Selective Agonist

Hoo-Sang Hwang, Hyuk-Jae Choi, Sang-Jip Nam, Jae-Young Ko, Jung-Yeob Ham, Jung-Wook Chin, Heon-Joong Kang
2011 Bulletin of the Korean Chemical Society (Print)  
Peroxisome Proliferator-Activated Receptor α (PPARα), a major regulator of energy homeostasis discovered in 1990, is present at high density in the liver and regulates the expression of genes involved in fatty acid β-oxidation. 1 As research on its function has been localized to animal experiments, the function of PPARα in humans is still unclear. Past studies revealed PPARα participation in tumorgenesis, 2 inflammation 3,4 and atherosclerosis. 5 Therefore, selective agonists of PPARα are
more » ... ed to be potential antitumor, anti-inflammatory and anti-atherosclerotic agents. Fibrates were the first generation of PPARα modulators ( Figure 1 ) GlaxoSmithKline (GSK) then developed a series of ureasubstituted thioisobutyric acids (ureido-TiBAs), 6 which were synthesized using a parallel-array synthetic method. Ureido-TiBA derivatives synthesized from the compounds GW7647 and GW9578 were found to be effective for heart disease caused by hypertension and high-cholesterol in vivo ( Figure 2) . In particular, GW7647 demonstrated superior potency with ~200-fold selectivity over the other PPAR subtypes (EC 50 = 6 nM for human PPARα). 6 In addition, the administration of GW7647 to rats for 4 days decreased triglyceride and serum apolipoprotein CIII levels by 60% and 40%, respectively, and increased HDL-cholesterol levels by 60%. In this note, we shortly and efficiently synthesized a novel isosteric selenium substitution of ureido-selenoisobutyric acid of the PPARα agonist and compared its PPARα activity. Isosterism is a useful strategy for molecular modification and is a rational approach in drug design. 7 Isosteric analogs possess an equally well-established biological potency in terms of protein-receptor interactions. 8 As a proof-of-concept, sulfur-selenium bioisosterism was applied to GW7647 because molecular modeling study suggested a bulkier element at the sulfur fit the receptor better. 9 During the course of one-pot synthetic studies of alkyl aryl selenides, we developed an in situ one-pot synthetic method that is used for the protection of the amine group in aryl bromides with alkylmagnesium bromide. 10,11 Thus, we set out to develop a method for the formation of an aryl alkyl selenide (such as compound 2) with an amine substituent that could be used to prepare various ureido-selenoisobutyric acids via a simple and efficient synthetic route. In our reaction, the starting material 1 is commercially available. 4-bromophenethylamine 6 is more expensive than 4-bromobenzeneselenol. But our protocol for preparing 2 is cheaper and shorter than that of the GSK protocol. 6 Although we could not directly detect the transition state during the reaction, intermediates for synthesis of the target Figure 1. Chemical structures of fibrate compounds. Figure 2. Chemical structures of GW7647 and GW9578, synthetic PPARα agonists.
doi:10.5012/bkcs.2011.32.11.4089 fatcat:ako3zefzq5f2ngnmtzl6zocbaq