Selective inhibition of aggrecanase in osteoarthritis treatment

摘要

This invention relates to a method of treatment for osteoarthritis involving inhibitors of aggrecanase that demonstrate IC₅₀s of less than 20 nM and demonstrate differential potency against matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs or reprolysins). This invention also relates to compounds, methods of treatment and composition of Formula I: or a therapeutically acceptable salt thereof, wherein X is carbon or nitrogen; R¹ and R² are independently selected from the group consisting of hydrogen, hydroxy, and methyl, wherein at least one of R¹ and R² is methyl; R³ and R⁴ are independently selected from the group consisting of hydrogen, hydroxy, and methyl, or R³ and R⁴ may be taken together to form a carbonyl group; and R⁵ and R⁶ are independent substituents in the ortho, meta, or para positions and are independently selected from the group consisting of hydrogen, halogen, cyano, methyl, and ethyl; with the provisos: when X is carbon, then R⁷ and R⁸ are both hydrogen and at least one of R¹, R², R³, and R⁴ is hydroxy; when X is carbon and R⁵ is para-halo, then at least one of R⁶, R³, and R⁴ is not hydrogen; when X is nitrogen, then R⁸ is not present and R⁷ is hydrogen or a group of the formula: wherein, Y is -CH₂-NH₂ or -NH-CH₃; and when X is nitrogen and R⁷ is H, then R³ and R⁴ are taken together to form a carbonyl group.