Discovery of novel indole derivatives as potent and selective inhibitors of proMMP-9 activation.

Matrix metalloproteinase-9 (MMP-9) is a secreted zinc-dependent endopeptidase that degrades the extracellular matrix and basement membrane of neurons, and then contributes to synaptic plasticity by remodeling the extracellular matrix. Inhibition of MMP-9 activity has therapeutic potential for neurodegenerative diseases such as fragile X syndrome. This paper reports the molecular design, synthesis, and in vitro studies of novel indole derivatives as inhibitors of proMMP-9 activation.

Design, synthesis and biological evaluation of novel indole derivatives as gut-selective NaPi2b inhibitors.

Intestinal sodium-dependent phosphate transport protein 2b (SLC34A2, NaPi2b) inhibitors are expected to be potential new candidates for anti-hyperphosphatemia drugs. However, a risk of on-target side effects based on the inhibition of NaPi2b in the lung and testis has been reported.In this article, we report on our identification of novel indole derivatives as gut-selective NaPi2b inhibitors with good activity, low systemic exposure and moderate hydrophobicity.

Design, synthesis and biological evaluation of novel pyridine derivatives as gut-selective NaPi2b inhibitors.

We previously reported thiophene derivatives as gut-selective (minimally systemic) and potent sodium-dependent phosphate transport protein 2b (SLC34A2, NaPi2b) inhibitors. However, these derivatives did not suppress phosphate absorption form the intestinal tract in Sprague-Dawley (SD) rats. The lack of efficacy in vivo could be due to the high hydrophobicity of these compounds.

Design, synthesis and biological evaluation of novel 1H-pyrazole-4-carbonyl-4,5,6,7-tetrahydrobenzo [b]thiophene derivatives as gut-selective NaPi2b inhibitors.

Intestinal sodium-dependent phosphate transport protein 2b (SLC34A2, NaPi2b) inhibitors are expected to be potential new candidates for anti-hyperphosphatemia drugs. However, a risk of on-target side effects based on the inhibition of NaPi2b in the lung and testis has been reported. To identify gut-selective (minimally systemic) NaPi2b inhibitors, we prepared and evaluated 1H-pyrazole-4-carbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene derivatives with highly polar functional groups to reduce systemic exposure.