Synthesis of a series of stromelysin-selective thiadiazole urea matrix metalloproteinase inhibitors

The synthesis and enzyme inhibition data for a series of thiadiazole urea m atrix metalloproteinase (MMP) inhibitors are described. A broad screening e ffort was utilized to identify several thiadiazoles which were weak inhibit ors of stromelysin. Optimization of the thiadiazole leads to include an alp ha-amino acid side chain with variable terminal amide substituents provided a series of ureas which were moderately effective stromelysin inhibitors, with K-i's between 0.3 and 1.0 mu M. The most effective analogues utilized an L-phenylalanine as the amino acid component. In particular, unsubstitute d 46 had a K-i of 710 nM, while the p-fluoro analogue 52 displayed increase d potency (100 nM). Stromelysin inhibition was further improved using a pen tafluorophenylalanine substituent which resulted in 70, a 14 nM inhibitor. While gelatinase inhibition was generally poor, the use of 1-(2-pyridyl)pip erazine as the amide component usually provided for enhanced activity, with 71 inhibiting gelatinase with a K-i of 770 nM. The combination of this het erocycle with a p-fluorophenylalanine substituent provided the only analogu e, 69, with collagenase activity (13 mu M). The SAR for analogues described within this series can be rationalized through consideration of the X-ray structure recently attained for 70 complexed to stromelysin. Uniquely, this structure showed the inhibitor to be completely orientated on the left sid e of the enzyme cleft. These results suggest that thiadiazole urea heterocy cles which incorporate a substituted phenylalanine can provide selective in hibitors of stromelysin. Careful selection of the amide substituent can als o provide for analogues with modest gelatinase inhibition.