N-(2-benzoylphenyl)-L-tyrosine PPAR gamma agonists. 2. Structure-activity relationship and optimization of the phenyl alkyl ether moiety

We previously reported the identification of (2S)-((2-benzoylphenyl)amino)- 3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propanoic (2) (PPAR gam ma pK(i) = 8.94, PPAR gamma, pEC(50) = 9.47) as a potent and selective PPAR gamma 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 synth esis. The solution-phase strategy focused on evaluating the effects of oxaz ole and phenyl ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)eth yl side chain of 2 with several replacements providing potent and selective PPAR gamma agonists with improved aqueous solubility. Specifically, replac ement 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-yloxaz ol-4-yl)ethoxy]phenyl}propionic acid (16) (PPAR gamma pK(i) = 8.85, PPAR ga mma pEC(50) = 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}phey nyl)propionic acid (24) (PPAR gamma pK(i) = 8.6, PPAR gamma pEC(50) = 8.89) provided two potent and selective PPAR gamma agonists with increased solub ility 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 so lid-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 PPAR gamma ligands (PPAR gamma pK(i)'s 6.98-8.03). The combined structure- activity data derived from the two strategies provide valuable insight on t he requirements for PPAR gamma binding, functional activity, selectivity, a nd aqueous solubility.