Abstract
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 vive 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.
Original language | English (US) |
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Pages (from-to) | 5020-5036 |
Number of pages | 17 |
Journal | Journal of Medicinal Chemistry |
Volume | 41 |
Issue number | 25 |
DOIs | |
State | Published - Dec 3 1998 |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery