Aryloxy-p-Phenyl Propionic Acids

These compounds belong to the class of a-aryloxy-p-phenyl propionic acids, the first dual PPAR inhibitors with an aryloxy group on the a-carbon in relation to the carboxylic group, represented by the lead compotmd, (S)-5. 

The first report of the synthesis and activity of these compounds as PPAR agonists concerned the biphenyl derivative 6 (Fig. 3.6) and its congeners [9, 10]. The crystal structure and activity of the two enantiomeric forms of 6, complexed with the ligandbinding domain (LED) of PPARy, provided a molecular explanation for their different potency and efficacy. Docking of the S-6 enantiomer in the PPARy-LBD was 

The 5-enantiomers of the 2-aryloxy derivatives 5 and 6 exhibited EC50 values of 0.15 pM and 0.22 pM, respectively, on PPARa, whereas in both cases, their -enantiomers proved inactive at the tested concentrations [6-11], 

compounds 5 and 6, two lead molecules within the class of hPPAR 2-aryloxy-3-phenyl propionic acid agonists, exhibit opposite enantiopreference for compound 1, the main object of our consideration in this chapter, which is also an 2-aryloxy-propionic acid derivative. Since, no details of the structure of the complex of 1 and the LBD of hPPARs were reported, it can be assumed that the absence of a phenyl group at position C(3) in 1 somehow results in inverse steric requirements for this agonist at LBD, when compared with its 3-phenyl congeners, 5 and 6. Since, the route to enantiomerically pure (R)-l includes a number of original synthetic solutions, a detailed discussion of these is presented in later sections. 

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