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N-(2-Benzoylphenyl)-l-tyrosine PPARγ 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 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 phe...

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Published in:Journal of medicinal chemistry 1998-12, Vol.41 (25), p.5037-5054
Main Authors: Collins, Jon L, Blanchard, Steven G, Boswell, G. Evan, Charifson, Paul S, Cobb, Jeff E, Henke, Brad R, Hull-Ryde, Emily A, Kazmierski, Wieslaw M, Lake, Debra H, Leesnitzer, Lisa M, Lehmann, Jürgen, Lenhard, James M, Orband-Miller, Lisa A, Gray-Nunez, Yolanda, Parks, Derek J, Plunkett, Kelli D, Tong, Wei-Qin
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cited_by cdi_FETCH-LOGICAL-a295t-98e4d969d62ca4a622acc09c2707b3e1af2216078914dc88d87440c01023d0da3
cites cdi_FETCH-LOGICAL-a295t-98e4d969d62ca4a622acc09c2707b3e1af2216078914dc88d87440c01023d0da3
container_end_page 5054
container_issue 25
container_start_page 5037
container_title Journal of medicinal chemistry
container_volume 41
creator Collins, Jon L
Blanchard, Steven G
Boswell, G. Evan
Charifson, Paul S
Cobb, Jeff E
Henke, Brad R
Hull-Ryde, Emily A
Kazmierski, Wieslaw M
Lake, Debra H
Leesnitzer, Lisa M
Lehmann, Jürgen
Lenhard, James M
Orband-Miller, Lisa A
Gray-Nunez, Yolanda
Parks, Derek J
Plunkett, Kelli D
Tong, Wei-Qin
description 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.
doi_str_mv 10.1021/jm980413z
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Evan ; Charifson, Paul S ; Cobb, Jeff E ; Henke, Brad R ; Hull-Ryde, Emily A ; Kazmierski, Wieslaw M ; Lake, Debra H ; Leesnitzer, Lisa M ; Lehmann, Jürgen ; Lenhard, James M ; Orband-Miller, Lisa A ; Gray-Nunez, Yolanda ; Parks, Derek J ; Plunkett, Kelli D ; Tong, Wei-Qin</creatorcontrib><description>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. 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Chem</addtitle><date>1998-12-03</date><risdate>1998</risdate><volume>41</volume><issue>25</issue><spage>5037</spage><epage>5054</epage><pages>5037-5054</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>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.</abstract><pub>American Chemical Society</pub><doi>10.1021/jm980413z</doi><tpages>18</tpages></addata></record>
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title N-(2-Benzoylphenyl)-l-tyrosine PPARγ Agonists. 2. Structure−Activity Relationship and Optimization of the Phenyl Alkyl Ether Moiety
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