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

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• 作者：Edward J. Hennessy ; Vibha Oza ; Ammar Adam ; Kate Byth ; Lillian Castriotta ; Gurmit Grewal ; Geraldine A. Hamilton ; Victor M. Kamhi ; Paula Lewis ; Danyang Li ; Paul Lyne ; Linda 脰ster ; Michael T. Rooney ; Jamal C. Saeh ; Li Sha ; Qibin Su ; Shengua Wen ; Yafeng Xue ; Bin Yang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 10, 2015
• 年：2015
• 卷：58
• 期：17
• 页码：7057-7075
• 全文大小：711K
• ISSN：1520-4804

文摘

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 渭M), but has poor physical properties and metabolic stability. Evolution of this compound through structure鈥揳ctivity 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.