N-(2-benzoylphenyl)-L-tyrosine PPARγ agonists.: 3.: Structure-activity relationship and optimization of the N-aryl substituent

3-{4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl}-(2S)-((2-benzoylphenyl)amino)propionic acid (1) and (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid (2) are peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of 1 and 2, a series of novel carboxylic acid analogues, 23-66, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPAR gamma agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of 1 and 2 are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two phenyl rings of this moiety. Addition of substituents to this moiety generally produced compounds that are less active in the cell-based functional assays of PPAR gamma activity although binding affinity to PPAR gamma may be maintained. A particularly promising set of analogues is the anthranilic acid esters 63-66 in which the phenyl ring in the 2-benzoyl group of 1 and 2 has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}ethylamino)benzoic acid methyl ester (63) has a pK(i) of 8.43 in the binding assay using human PPAR gamma ligand binding domain and a pEC(50) of 9.21 in the in vitro murine lipogenesis functional assay of PPAR gamma activity. Finally, 63 was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.