Identification and Optimization of Benzimidazole Sulfonamides
as Orally Bioavailable Sphingosine 1‑Phosphate Receptor 1 Antagonists with in Vivo
Activity
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Abstract
We
report here a novel series of benzimidazole sulfonamides that
act as antagonists of the S1P<sub>1</sub> receptor, identified by
exploiting an understanding of the pharmacophore of a high throughput
screening (HTS)-derived series of compounds described previously.
Lead compound <b>2</b> potently inhibits S1P-induced receptor
internalization in a cell-based assay (EC<sub>50</sub> = 0.05 μM),
but has poor physical properties and metabolic stability. Evolution
of this compound through structure–activity relationship development
and property optimization led to <i>in vivo</i> probes such
as <b>4</b>. However, this compound was unexpectedly found to
be a potent CYP3A inducer in human hepatocytes, and thus further chemistry
efforts were directed at addressing this liability. By employing a
pregnane X receptor (PXR) reporter gene assay to prioritize compounds
for further testing in human hepatocytes, we identified lipophilicity
as a key molecular property influencing the likelihood of P450 induction.
Ultimately, we have identified compounds such as <b>46</b> and <b>47</b>, which demonstrate the desired S1P<sub>1</sub> antagonist
activity while having greatly reduced risk of CYP3A induction in humans.
These compounds have excellent oral bioavailability in preclinical
species and exhibit pharmacodynamic effects of S1P<sub>1</sub> antagonism
in several <i>in vivo</i> models following oral dosing.
Relatively modest antitumor activity was observed in multiple xenograft
models, however, suggesting that selective S1P<sub>1</sub> antagonists
would have limited utility as anticancer therapeutics as single agents