4 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 and Optimization of a Novel Series of Potent Mutant B‑Raf<sup>V600E</sup> Selective Kinase Inhibitors
B-Raf
represents an attractive target for anticancer therapy and
the development of small molecule B-Raf inhibitors has delivered new
therapies for metastatic melanoma patients. We have discovered a novel
class of small molecules that inhibit mutant B-Raf<sup>V600E</sup> kinase activity both in vitro and in vivo. Investigations into the
structure–activity relationships of the series are presented
along with efforts to improve upon the cellular potency, solubility,
and pharmacokinetic profile. Compounds selectively inhibited B-Raf<sup>V600E</sup> in vitro and showed preferential antiproliferative activity
in mutant B-Raf<sup>V600E</sup> cell lines and exhibited selectivity
in a kinase panel against other kinases. Examples from this series
inhibit growth of a B-Raf<sup>V600E</sup> A375 xenograft in vivo at
a well-tolerated dose. In addition, aminoquinazolines described herein
were shown to display pERK elevation in nonmutant B-Raf cell lines
in vitro
Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors
Janus
kinases (JAKs) have been demonstrated to be critical in cytokine signaling
and have thus been implicated in both cancer and inflammatory diseases.
The JAK family consists of four highly homologous members: JAK1–3
and TYK2. The development of small-molecule inhibitors that are selective
for a specific family member would represent highly desirable tools
for deconvoluting the intricacies of JAK family biology. Herein, we
report the discovery of a potent JAK1 inhibitor, 24, which displays
∼1000-fold selectivity over the other highly homologous JAK
family members (determined by biochemical assays), while also possessing
good selectivity over other kinases (determined by panel screening).
Moreover, this compound was demonstrated to be orally bioavailable
and possesses acceptable pharmacokinetic parameters. In an in vivo
study, the compound was observed to dose dependently modulate the
phosphorylation of STAT3 (a downstream marker of JAK1 inhibition)