N-(2-Benzoylphenyl)-l-tyrosine PPARγ Agonists. 1. Discovery of a Novel Series of Potent Antihyperglycemic and Antihyperlipidemic Agents

• Published in: Journal of medicinal chemistry Vol. 41; no. 25; pp. 5020 - 5036
• Main Authors: Henke, Brad R, Blanchard, Steven G, Brackeen, Marcus F, Brown, Kathleen K, Cobb, Jeff E, Collins, Jon L, Harrington, W. Wallace, Hashim, Mir A, Hull-Ryde, Emily A, Kaldor, Istvan, Kliewer, Steven A, Lake, Debra H, Leesnitzer, Lisa M, Lehmann, Jürgen M, Lenhard, James M, Orband-Miller, Lisa A, Miller, John F, Mook, Robert A, Noble, Stewart A, Oliver, William, Parks, Derek J, Plunket, Kelli D, Szewczyk, Jerzy R, Willson, Timothy M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 03-12-1998
• Subjects: Biological and medical sciences; General and cellular metabolism. Vitamins; Medical sciences; Pharmacology. Drug treatments; Endocrinopathy; Agonist; Rat; Nitrogen heterocycle; Non insulin dependent diabetes; Peroxisome proliferator; Pyridine derivatives; Hypoglycemic agent; Structure activity relation; Transcription factor; Chemical synthesis; Oxazole derivatives; Oxygen nitrogen heterocycle; Biological receptor; Benzoxazole derivatives; Rodentia; Benzene derivatives; Oral administration; In vitro; In vivo; α-Aminoacid; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Animal; Affinity; Antilipemic agent
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9804127

We have identified a novel series of antidiabetic N-(2-benzoylphenyl)-l-tyrosine derivatives which are potent, selective PPARγ agonists. Through the use of in vitro PPARγ binding and functional assays (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)amino)propionic acid (2) was identified as a structurally novel PPARγ 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 PPARγ, affording a series of potent and selective PPARγ 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-benzoylphenyl)amino)propanoic acid (19), and (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]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 PPARγ agonists relative to troglitazone may translate into superior clinical efficacy for the treatment of type 2 diabetes.