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 <b>2</b> 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 <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 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 <i>in vivo</i> 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

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 <b>2</b> 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 <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 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 <i>in vivo</i> 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

Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3‑Kinase (PI3K)‑γ Inhibitors

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as <b>15</b>, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound <b>15</b> was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally

Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3‑Kinase (PI3K)‑γ Inhibitors

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as <b>15</b>, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound <b>15</b> was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally