Molecular dynamics study-guided identification of cyclic amine structures as novel hydrophobic tail components of hPPARγ agonists.

Abstract We previously reported that a α-benzylphenylpropanoic acid-type hPPARγ-selective agonist with a piperidine ring as the hydrophobic tail part ( 3 ) exhibited sub-micromolar-order hPPARγ agonistic activity. In order to enhance the activity, we planned to carry out structural development based on information obtained from the X-ray crystal structure of hPPARγ ligand binding domain (LBD) complexed with 3 . However, the shape and/or nature of the binding pocket surrounding the piperidine ring of 3 could not be precisely delineated because the structure of the omega loop of the LBD was poorly defined. Therefore, we constructed and inserted a plausible omega loop by means of molecular dynamics simulation. We then used the reconstructed LBD structure to design new mono-, bi- and tricyclic amine-bearing compounds that might be expected to show greater binding affinity for the LBD. Here, we describe synthesis and evaluation of α-benzylphenylpropanoic acid derivatives 8 . As expected, most of the newly synthesized compounds exhibited more potent hPPARγ agonistic activity and greater hPPARγ binding affinity than 3 . Some of these compounds also showed comparable aqueous solubility to 3 .