Development of new hydroxamate matrix metalloproteinase inhibitors derivedfrom functionalized 4-aminoprolines

A series of hydroxamates was prepared from an aminoproline scaffold and tes ted for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a n umber of inhibitors, such as compound 47, display broad-spectrum activity w ith sub-nanomolar potency for some enzymes. Modifications of the P1' portio n of the molecule played a key role in affecting both potency and selectivi ty within the MMP family. Longer-chain aliphatic substituents in this regio n of the molecule tended to increase potency for MMP-3 and decrease potency for MMP-1, as exemplified by compounds 48-50, while aromatic substituents, as in compound 52, generated broad-spectrum inhibition. The data is ration alized based upon X-ray crystal data which is also presented. While the in vitro peroral absorption seemed to be less predictable, it tended to decrea se with longer and more hydrophilic substituents. Finally, a rat model of o steoarthritis was used to evaluate the efficacy of these compounds, and a d irect link was established between their pharmacokinetics and their in vivo efficacy.