3 research outputs found
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 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
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 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
Discovery of a Novel Class of Dimeric Smac Mimetics as Potent IAP Antagonists Resulting in a Clinical Candidate for the Treatment of Cancer (AZD5582)
A series of dimeric compounds based
on the AVPI motif of Smac were
designed and prepared as antagonists of the inhibitor of apoptosis
proteins (IAPs). Optimization of cellular potency, physical properties,
and pharmacokinetic parameters led to the identification of compound <b>14</b> (AZD5582), which binds potently to the BIR3 domains of
cIAP1, cIAP2, and XIAP (IC<sub>50</sub> = 15, 21, and 15 nM, respectively).
This compound causes cIAP1 degradation and induces apoptosis in the
MDA-MB-231 breast cancer cell line at subnanomolar concentrations
in vitro. When administered intravenously to MDA-MB-231 xenograft-bearing
mice, <b>14</b> results in cIAP1 degradation and caspase-3 cleavage
within tumor cells and causes substantial tumor regressions following
two weekly doses of 3.0 mg/kg. Antiproliferative effects are observed
with <b>14</b> in only a small subset of the over 200 cancer
cell lines examined, consistent with other published IAP inhibitors.
As a result of its in vitro and in vivo profile, <b>14</b> was
nominated as a candidate for clinical development