N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents.
We have identified a novel series of antidiabetic N-(2-benzoylphenyl)-L-tyrosine derivatives which are potent, selective PPARgamma agonists. Through the use of in vitro PPARgamma binding and functional assays (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)+ ++amin o)propionic acid (2) was identified as a structurally novel PPARgamma agonist. Structure-activity relationships identified the 2-aminobenzophenone moiety as a suitable isostere for the chemically labile enaminone moiety in compound 2, affording 2-((2-benzoylphenyl)amino)-3-(4-(benzyloxy)phenyl)propionic acid (9). Replacement of the benzyl group in 9 with substituents known to confer in vivo potency in the thiazolidinedione (TZD) class of antidiabetic agents provided a dramatic increase in the in vitro functional potency and affinity at PPARgamma, affording a series of potent and selective PPARgamma agonists exemplified by (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(methylpyridin-2-ylamino+ ++)ethoxy ]phenyl¿propionic acid (18), 3-¿4-[2-(benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propanoic acid (19), and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propanoic acid (20). Compounds 18 and 20 show potent antihyperglycemic and antihyperlipidemic activity when given orally in two rodent models of type 2 diabetes. In addition, these analogues are readily prepared in chiral nonracemic fashion from L-tyrosine and do not show a propensity to undergo racemization in vitro. The increased potency of these PPARgamma agonists relative to troglitazone may translate into superior clinical efficacy for the treatment of type 2 diabetes.
Henke
B R
BR
Glaxo Wellcome Research and Development, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA. brh14990@glaxowellcome.com
Blanchard
S G
SG
Brackeen
M F
MF
Brown
K K
KK
Cobb
J E
JE
Collins
J L
JL
Harrington
W W
WW
Hashim
M A
MA
Hull-Ryde
E A
EA
Kaldor
I
I
Kliewer
S A
SA
Lake
D H
DH
Leesnitzer
L M
LM
Lehmann
J M
JM
Lenhard
J M
JM
Orband-Miller
L A
LA
Miller
J F
JF
Mook
R A
RA
Noble
S A
SA
Oliver
W
W
Parks
D J
DJ
Plunket
K D
KD
Szewczyk
J R
JR
Willson
T M
TM
D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000819:agonists*; D003921:Diabetes Mellitus, Experimental / Q000097:blood; 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; D008297:Male; D051379:Mice; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000819:agonists / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C116280:2-((2-benzoylphenyl)amino)-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic acid; C116279:2-((2-benzoylphenyl)amino)-3-(4-(2-(methylpyridin-2-ylamino)ethoxy)phenyl)propionic acid; D000631:Aminopyridines; D001786:Blood Glucose; 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; D014157:Transcription Factors; D014443:Tyrosine