Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
J Med Chem. 2010 Dec 9;53(23):8421-39. doi: 10.1021/jm101288t. Epub 2010 Nov 11.
New heterocyclic analogues of the potent biphenyl class derived from antitubercular drug PA-824 were prepared, aiming to improve aqueous solubility but maintain high metabolic stability and efficacy. The strategy involved replacement of one or both phenyl groups by pyridine, pyridazine, pyrazine, or pyrimidine, in order to reduce lipophilicity. For para-linked biaryls, hydrophilicities (ClogP) correlated with measured solubilities, but highly soluble bipyridine analogues displayed weak antitubercular activities. A terminal pyridine or proximal heterocycle allowed retention of potency and provided solubility improvements, particularly at low pH, with examples from the latter classes displaying the better in vivo efficacies, high metabolic stabilities, and excellent pharmacokinetics. Five such compounds were >100-fold better than the parent drug in a mouse model of acute Mycobacterium tuberculosis infection, and two orally bioavailable pyridine analogues (3-4-fold more soluble than the parent at low pH) were superior to antitubercular drug OPC-67683 in a chronic infection model.
我们合成了新型杂环类似物，这些类似物源于抗结核药物 PA-824，旨在提高水溶性，同时保持高代谢稳定性和疗效。该策略涉及用吡啶、哒嗪、吡嗪或嘧啶取代一个或两个苯基，以降低脂溶性。对于对位连接的联苯，亲水性（ClogP）与测量的溶解度相关，但高水溶性的联吡啶类似物显示出较弱的抗结核活性。末端吡啶或近端杂环可以保留活性并提供溶解度的改善，特别是在低 pH 值下，后一类的例子显示出更好的体内疗效、高代谢稳定性和优异的药代动力学。在急性结核分枝杆菌感染的小鼠模型中，有 5 种此类化合物比母体药物好 100 多倍，而两种口服生物利用度的吡啶类似物（在低 pH 值下比母体药物溶解度高 3-4 倍）在慢性感染模型中优于抗结核药物 OPC-67683。
