Novel malonamide derivatives as alpha(v)beta(3) antagonists. Syntheses andevaluation of 3-(3-indolin-1-yl-3-oxopropanoyl)aminopropanoic acids on vitronectin interaction with alpha(v)beta(3)

In attempt to find novel integrin alpha (v)beta (3) antagonists, we selecte d SC65811 and its guanidine analogue (1) as lead compounds. Modification of the glycine part of SC65811 led to a new series of malonamide derivatives that exhibited alpha (v) beta (3) inhibitory activity. Among them, (R,S)-3- {3-[6-(3-benzylureido)indolin-1-yl]-3-oxopropanoylamino}-3-(pyridin-3-yl)pr opanoic acid (43a) showed not only potent activity with an IC50 value of 3. 0 nM but also good selectivity for alpha (v)beta (3) relative to alpha (IIb )beta (3), alpha (5)beta (1), and alpha (v)beta (5) with IC50 values of 190 00, 11000, and 14nM, respectively. Furthermore, optimization of 43a led to the most potent alpha (v)beta (3) antagonist, (R,S)-3-(3-16-[(4,5-dihydro-1 H-imidazol-2-yl)amino]indolin-1-yl}-3-oxopropanoylamino)-3-(quinolin-3-yl)p ropanoic acid (431) with an IC50 value of 0.42 nM. The synthesis and the st ructure-activity relationships of these malonamide derivatives are presente d.