We previously reported the discovery of pyrimido-pyrrolo-quinoxalinedione (PPQ) inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and showed their efficacy in an organ culture model of polycystic kidney disease (PKD) ( J. Med. Chem. 2009, 52, 6447−6455). Here, we report related benzopyrimido-pyrrolo-oxazinedione (BPO) CFTR inhibitors. To establish structure–activity relationships and select lead compound(s) with improved potency, metabolic stability, and aqueous solubility compared to the most potent prior compound 8 (PPQ-102, IC₅₀ ∼ 90 nM), we synthesized 16 PPQ analogues and 11 BPO analogues. The analogues were efficiently synthesized in 5–6 steps and 11–61% overall yield. Modification of 8 by bromine substitution at the 5-position of the furan ring, replacement of the secondary amine with an ether bridge, and carboxylation, gave 6-(5-bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11-phenyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrimido [4′,5′:3,4]pyrrolo [1,2-d][1,4]oxazine-2-carboxylic acid 42 (BPO-27), which fully inhibited CFTR with IC₅₀ ∼ 8 nM and, compared to 8, had >10-fold greater metabolic stability and much greater polarity/aqueous solubility. In an embryonic kidney culture model of PKD, 42 prevented cyst growth with IC₅₀ ∼ 100 nM. Benzopyrimido-pyrrolo-oxazinediones such as 42 are potential development candidates for antisecretory therapy of PKD.

中文翻译：

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用于多囊肾病的强效、代谢稳定的苯并嘧啶并吡咯并恶嗪二酮 (BPO) CFTR 抑制剂

我们之前报道了囊性纤维化跨膜电导调节剂 (CFTR) 氯通道的嘧啶-吡咯并-喹喔啉二酮 (PPQ) 抑制剂的发现，并在多囊肾病 (PKD) 的器官培养模型中显示了它们的功效 ( J. Med. Chem. 2009 , 52 , 6447-6455)。在这里，我们报告了相关的苯并嘧啶-吡咯并-恶嗪二酮 (BPO) CFTR 抑制剂。建立结构-活性关系并选择与最有效的先前化合物8 (PPQ-102, IC ₅₀₎相比具有更高效力、代谢稳定性和水溶性的先导化合物∼ 90 nM)，我们合成了 16 个 PPQ 类似物和 11 个 BPO 类似物。类似物在 5-6 步中有效合成，总产率为 11-61%。的变形例8由溴取代的呋喃环的5-位，更换新的仲胺用醚桥，和羧基化，得到6-（5-溴呋喃-2-基）-7,9-二甲基-8-， 10-dioxo-11-phenyl-7,8,9,10-tetrahydro-6 H - benzo[ b ]pyrimido [4',5':3,4]pyrrolo [1,2- d ][1,4]恶嗪-2-羧酸42 (BPO-27)，完全抑制 CFTR，IC ₅₀ ∼ 8 nM，与8，具有>10 倍的代谢稳定性和更大的极性/水溶性。在 PKD 的胚胎肾培养模型中，42以 IC ₅₀ ∼ 100 nM阻止囊肿生长。苯并嘧啶-吡咯-恶嗪二酮（例如42）是 PKD 抗分泌治疗的潜在开发候选物。