Influence of N-arylsulfonamido d-valine N-substituents on the selectivity and potency of matrix metalloproteinase inhibitors.

[Display omitted] • Eighteen N -substituted N -arylsulfonamido d -valines were synthesized and considered for both therapeutic application and medicinal imaging. • Most of these compounds proved to be nanomolar inhibitors particularly for gelatinases MMP-2 and MMP-9. • Generally, the compounds are less potent inhibitors of collagenases (MMP-8 and MMP-13) and macrophage elastase (MMP-12) • Linking a terminal fluoroalkyltriazole moiety at the P1′ substituent did not significantly lower the inhibition potential, but opens an opportunity for 18F-labeling and PET imaging. • Linking a fluorescein moiety (P2′ substituent) at the sulfonamide nitrogen via a triethyleneglycol spacer led to a highly potent probe for fluorescence imaging. To develop matrix metalloproteinase inhibitors (MMPIs) for both therapy and medicinal imaging by fluorescence-based techniques or positron-emission tomography (PET), a small library of eighteen N -substituted N -arylsulfonamido d -valines were synthesized and their potency to inhibit two gelatinases (MMP-2, and MMP-9), two collagenases (MMP-8, and MMP-13) and macrophage elastase (MMP-12) was determined in a Structure-Activity-Relation study with ({4-[3-(5-methylthiophen-2-yl)-1,2,4-oxadiazol-5-yl]phenyl}sulfonyl)- d -valine (1) as a lead. All compounds were shown to be more potent MMP-2/-9 inhibitors (nanomolar range) compared to other tested MMPs. This is a remarkable result considering that a carboxylic acid group is the zinc binding moiety. The compound with a terminal fluoropropyltriazole group at the furan ring (P1′ substituent) was only four times less potent in inhibiting MMP-2 activity than the lead compound 1, making this compound a promising probe for PET application (after using a prosthetic group approach to introduce fluorine-18). Compounds with a TEG spacer and a terminal azide or even a fluorescein moiety at the sulfonylamide N atom (P2′ substituent) were almost as active as the lead structure 1 , making the latter derivative a suitable fluorescence imaging tool. [ABSTRACT FROM AUTHOR]