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, whereinX 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; andR5 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; andwhen X is
nitrogen and R7 is H, then R3 and R4 are taken together to form a
carbonyl group.