We previously reported the identification of (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propanoic acid (2) (PPARγ pK_i = 8.94, PPARγ pEC₅₀ = 9.47) as a potent and selective PPARγ agonist. We now report the expanded structure−activity relationship around the phenyl alkyl ether moiety by pursuing both a classical medicinal chemistry approach and a solid-phase chemistry approach for analogue synthesis. The solution-phase strategy focused on evaluating the effects of oxazole and phenyl ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of 2 with several replacements providing potent and selective PPARγ agonists with improved aqueous solubility. Specifically, replacement of the phenyl ring of the phenyloxazole moiety with a 4-pyridyl group to give 2(S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-pyridin-4-yloxazol-4-yl)ethoxy]phenyl}propionic acid (16) (PPARγ pK_i = 8.85, PPARγ pEC₅₀ = 8.74) or a 4-methylpiperazine to give 2(S)-((2-benzoylphenyl)amino)-3-(4-{2-[5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl]ethoxy}phenyl)propionic acid (24) (PPARγ pK_i = 8.66, PPARγ pEC₅₀ = 8.89) provided two potent and selective PPARγ agonists with increased solubility in pH 7.4 phosphate buffer and simulated gastric fluid as compared to 2. The second strategy took advantage of the speed and ease of parallel solid-phase analogue synthesis to generate a more diverse set of phenyl alkyl ethers which led to the identification of a number of novel, high-affinity PPARγ ligands (PPARγ pK_i's 6.98−8.03). The combined structure−activity data derived from the two strategies provide valuable insight on the requirements for PPARγ binding, functional activity, selectivity, and aqueous solubility.

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