5A86

Structure of pregnane X receptor in complex with a Sphingosine 1- Phosphate Receptor 1 Antagonist

5A86 の概要

• エントリーDOI: 10.2210/pdb5a86/pdb
• 分子名称: NUCLEAR RECEPTOR SUBFAMILY 1 GROUP I MEMBER 2, NUCLEAR RECEPTOR COACTIVATOR 1, 4-chloro-N-[(1R)-1-[1-ethyl-6-(trifluoromethyl)benzimidazol-2-yl]ethyl]benzenesulfonamide, ... (4 entities in total)
• 機能のキーワード: signaling protein, pxr ligand, pxr agonist, cyp3a4 induction, nuclear receptor
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• 細胞内の位置: Nucleus : O75469 Q15788
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 77181.86

構造登録者

Xue, Y.,Oster, L. (登録日: 2015-07-13, 公開日: 2015-10-21, 最終更新日: 2024-05-08)

主引用文献

Hennessy, E.J.,Oza, V.B.,Adam, A.,Byth, K.,Castriotta, L.,Grewal, G.,Hamilton, G.,Kamhi, V.M.,Lewis, P.,Li, D.,Lyne, P.D.,Oster, L.,Rooney, M.T.,Saeh, J.C.,Sha, L.,Su, Q.,Wen, S.,Xue, Y.,Yang, B.
Identification and Optimization of Benzimidazole Sulfonamides as Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists with in Vivo Activity.
J.Med.Chem., 58:7057-, 2015

PubMed Abstract: 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.

PubMed: 26291341
DOI: 10.1021/ACS.JMEDCHEM.5B01078

実験手法

X-RAY DIFFRACTION (2.25 Å)