N-(2-Benzoylphenyl)-L-tyrosine PPARgamma 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-y l)e thoxy]phenyl¿propanoic acid (2) (PPARgamma pKi = 8.94, PPARgamma pEC50 = 9.47) as a potent and selective PPARgamma 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 PPARgamma 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) (PPARgamma pKi = 8.85, PPARgamma 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) (PPARgamma pKi = 8.66, PPARgamma pEC50 = 8.89) provided two potent and selective PPARgamma 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 PPARgamma ligands (PPARgamma pKi's 6.98-8.03). The combined structure-activity data derived from the two strategies provide valuable insight on the requirements for PPARgamma binding, functional activity, selectivity, and aqueous solubility.
Collins
J L
JL
Glaxo Wellcome Research and Development, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA. jlc@glaxowellcome.com
Blanchard
S G
SG
Boswell
G E
GE
Charifson
P S
PS
Cobb
J E
JE
Henke
B R
BR
Hull-Ryde
E A
EA
Kazmierski
W M
WM
Lake
D H
DH
Leesnitzer
L M
LM
Lehmann
J
J
Lenhard
J M
JM
Orband-Miller
L A
LA
Gray-Nunez
Y
Y
Parks
D J
DJ
Plunkett
K D
KD
Tong
W Q
WQ
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000819:agonists*; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008055:Lipids / Q000096:biosynthesis; D051379:Mice; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000819:agonists / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C116281:2-((2-benzoylphenyl)amino)-3--(4-(2-(5-methyl-2-pyridin-4-yloxazol-4-yl)ethoxy)phenyl)propionic acid; C116282:2-((2-benzoylphenyl)amino)-3--(4--(2-(5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)ethoxy)phenyl)propionic acid; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D008024:Ligands; D008055:Lipids; D010080:Oxazoles; D011422:Propionates; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D013844:Thiazoles; D014157:Transcription Factors; D014443:Tyrosine