Identification and Optimization of Benzimidazole Sulfonamides as Orally Bioavailable Sphingosine 1‑Phosphate Receptor 1 Antagonists with in Vivo Activity

We
report here a novel series of benzimidazole sulfonamides that
act as antagonists of the S1P1 receptor, identified by
exploiting an understanding of the pharmacophore of a high throughput
screening (HTS)-derived series of compounds described previously.
Lead compound 2 potently inhibits S1P-induced receptor
internalization in a cell-based assay (EC50 = 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 in vivo probes such
as 4. 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 46 and 47, which demonstrate the desired S1P1 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 S1P1 antagonism
in several in vivo models following oral dosing.
Relatively modest antitumor activity was observed in multiple xenograft
models, however, suggesting that selective S1P1 antagonists
would have limited utility as anticancer therapeutics as single agents.