Targeted Fluoro Positioning for the Discovery of a Potent and Highly Selective Matrix Metalloproteinase Inhibitor

Abstract

The incorporation of fluorine atoms into functional molecules is of wide interest in synthetic organic chemistry as well as cognate disciplines. In particular, in medicinal chemistry, there is a strong desire to positively influence the physicochemical molecular properties of drug compounds by introducing fluorine into biologically active molecules. Here, we present targeted fluoro positioning as the key design principle of converting a weak matrix metalloproteinase‐13 (MMP‐13) inhibitor into a very potent (IC 50=6 nm) and highly selective (selectivity factors of >1000 over MMP‐1, 2, 3, 7, 8, 9, 10, 12, 14) inhibitor with excellent plasma and microsomal stability, and no binding to the hERG channel (hERG: human ether‐a‐go‐go related gene).

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

“…Further development of 56 yielded fluorinated compound 57 , which shares a similar binding geometry in molecular modeling experiments. Alteration of the substitution pattern of the aliphatic linker from meta to para at the entrance of the S1′ pocket and implementation of a fluorine atom within the S1′* loop resulted in a highly potent MMP‐13 inhibitor with an IC 50 value of 6 n m . Inhibitor 57 (Figure ) possesses outstanding selectivity factors of >1000 against MMP‐1, ‐2, ‐3, ‐7, ‐8, ‐9, ‐10, ‐12, and ‐14.…”

“…In vitro ADME (absorption, distribution, metabolism, and excretion) properties were determined and 57 proved to be highly stable in mouse plasma and mouse liver microsomes, with t 1/2 >240 min for both. Measurements of hERG inhibition revealed no hERG‐related liability for drug toxicity …”

“…Alteration of the substitutionp attern of the aliphatic linker from meta to para at the entrance of the S1' pocket and implementation of af luorine atom within the S1'*l oop resulted in ah ighly potent MMP-13 inhibitor with an IC 50 value of 6nm. [157] Inhibitor 57 ( Figure 28) possesses outstandings electivityf actors of > 1000 against MMP-1, -2, -3, -7, -8, -9, -10, -12, and -14. In vitro ADME (absorption, distribution, metabolism, and excretion) properties were determined and 57 provedt ob eh ighly stable in mouse plasma and mouse liver microsomes, with t 1/2 > 240 min for both.…”

“…Measurements of hERG inhibition revealed no hERG-related liability for drug toxicity. [157] At Ta keda,N ara and co-workers appliedt he strategy of connectingazinc-binding group to two of their previously described non-zinc-binding MMP-13 inhibitors. [158,159] Compound 58 ( Figure 28) resulted from structure-based design,f or which an on-zinc-binding fragment populating the S1' pocket was used as as tarting point.…”

Surface‐Active Fluorinated Quantum Dots for Enhanced Cellular Uptake

“…[17] In addition, the impact of fluorine atoms on the interaction of bioactive molecules with cells is profound,m ainly due to its high hydrophobicity.I ndeed, it is not ac oincidence that fluorine is present in around 20 %o fc urrentp harmaceutical compounds, and most of the optimizationp rocess in drug development is focused on the modification of activec ompounds with fluorine atoms. [18][19][20] In spite of this, the modification of NPs with fluorinated ligands to increase their hydrophobicity and exploit the effect of fluorine on the interactions with cells has been poorly investigated, and little is known aboutthe cellular uptake of fluorinated NPs. [21] Here, we reportt he fluorination of NPs as as traightforward strategy to modulate their interactions with cells and subsequent cellular uptake.…”