High-Potency Phenylquinoxalinone Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Activators

We
previously identified phenylquinoxalinone CFTRact-J027
(4) as a cystic fibrosis transmembrane conductance
regulator (CFTR) activator with an EC50 of ∼200
nM and demonstrated its therapeutic efficacy in mouse models of constipation.
Here, structure–activity studies were done on 36 synthesized
phenylquinoxalinone analogs to identify compounds with improved potency
and altered metabolic stability. Synthesis of the phenylquinoxalinone
core was generally accomplished by condensation of 1,2-phenylenediamines
with substituted phenyloxoacetates. Structure–activity studies
established, among other features, the privileged nature of a properly
positioned nitro moiety on the 3-aryl group. Synthesized analogs showed
improved CFTR activation potency compared to 4 with EC50 down to 21 nM and with greater metabolic stability. CFTR
activators have potential therapeutic indications in constipation,
dry eye, cholestatic liver diseases, and inflammatory lung disorders.

我们此前已将苯基喹喔啉酮类化合物CFTRact-J027（4）鉴定为囊性纤维化跨膜传导调节因子（cystic fibrosis transmembrane conductance regulator，CFTR）激活剂，其半数有效浓度（EC50）约为200纳摩尔（nM），并证实其在便秘小鼠模型中具备治疗功效。本研究针对36种合成的苯基喹喔啉酮类衍生物开展构效关系研究，以期筛选出活性更优且代谢稳定性得以优化的化合物。苯基喹喔啉酮母核的合成通常可通过1,2-苯二胺与取代苯基氧代乙酸酯的缩合反应实现。构效关系研究明确，除其他特征外，3-芳基环上处于合适位置的硝基基团具有独特优势。所合成的衍生物相较化合物4，CFTR激活活性显著提升，EC50最低可降至21 nM，且代谢稳定性更佳。CFTR激活剂在便秘、干眼症、胆汁淤积性肝病以及炎症性肺疾病中具备潜在治疗适应证。