Discovery of TP0628103: A Highly Potent and Selective MMP‑7 Inhibitor with Reduced OATP-Mediated Clearance Designed by Shifting Isoelectric Points

Matrix metalloproteinase-7 (MMP-7) has been shown to
play an important
role in pathophysiological processes such as cancer and fibrosis.
We previously discovered selective MMP-7 inhibitors by molecular hybridization
and structure-based drug design. However, the systemic clearance (CLtot) of the biologically active lead compound was very high.
Because our studies revealed that hepatic uptake by organic anion
transporting polypeptide (OATP) was responsible for the high CLtot, we found a novel approach to reducing their uptake based
on isoelectric point (IP) values as an indicator for substrate recognition
by OATP1B1/1B3. Our “IP shift strategy” to adjust the
IP values culminated in the discovery of TP0628103 (18), which is characterized by reduced in vitro OATP-mediated
hepatic uptake and in vivo CLtot. Our in vitro–in vivo extrapolation of
OATP-mediated clearance and the “IP shift strategy”
provide crucial insights for a new medicinal chemistry approach to
reducing the systemic clearance of OATP1B1/1B3 substrates.