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

; (). Targeted Fluoro Positioning for the Discovery of a Potent and Highly Selective Matrix Metalloproteinase Inhibitor. ChemistryOpen, 6, 2. DOI: 10.1002/open.201600158. Peer reviewed.

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 fluo-
rine 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 (IC50 = 6nM) 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).