Design, synthesis and anti-tuberculosis activity of 1-adamantyl-3-heteroaryl ureas with improved in vitro pharmacokinetic properties.
Design, synthesis and anti-tuberculosis activity of 1-adamantyl-3-heteroaryl ureas with improved in vitro pharmacokinetic properties.
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DOI：
10.1016/j.bmc.2013.02.028
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发表时间：
2013-05-01
影响因子：
3.5
通讯作者：
Lee RE
中科院分区：
文献类型：
--
作者：
North EJ;Scherman MS;Bruhn DF;Scarborough JS;Maddox MM;Jones V;Grzegorzewicz A;Yang L;Hess T;Morisseau C;Jackson M;McNeil MR;Lee RE
在突出的全球疾病中，结核病（TB）仍然是全世界由于传染病导致死亡的主要原因之一。开发缩短目前结核病治疗时间并对耐药菌株具有活性的新药至关重要。为了实现这些目标，我们集中精力开发具有1-金刚烷基-3-苯基脲一般结构的新型抗TB化合物。该系列对分枝杆菌有活性，并且发现先前的先导化合物抑制膜转运蛋白MmpL 3，该蛋白负责分枝菌酸跨质膜转运。然而，这些化合物的体外药代动力学（PK）特征较差，并且它们具有与人可溶性环氧化物水解酶（SEH）抑制剂相似的结构/SAR。因此，在本研究中，这类化合物的进一步优化由三个因素驱动：1）增加抗TB活性相对于人sEH活性的选择性，2）优化PK特征，包括溶解度和3）维持靶标抑制。以吡啶、嘧啶、三嗪、恶唑、异恶唑、恶二唑和吡唑取代原有1-金刚烷基-3-杂芳基脲中的苯基取代基，设计合成了一系列新的1-金刚烷基-3-杂芳基脲。该研究生产了具有改善的体外PK特征、增加的选择性和良好的抗TB效力且最小抑制浓度低于µg/mL的铅恶二唑和吡唑取代的金刚烷基脲。
Out of the prominent global ailments, tuberculosis (TB) is still one of the leading causes of death worldwide due to infectious disease. Development of new drugs that shorten the current tuberculosis treatment time and have activity against drug resistant strains is of utmost importance. Towards these goals we have focused our efforts on developing novel anti-TB compounds with the general structure of 1-adamantyl-3-phenyl urea. This series is active against Mycobacteria and previous lead compounds were found to inhibit the membrane transporter MmpL3, the protein responsible for mycolic acid transport across the plasma membrane. However, these compounds suffered from poor in vitro pharmacokinetic (PK) profiles and they have a similar structure/SAR to inhibitors of human soluble epoxide hydrolase (SEH) enzymes. Therefore, in this study the further optimization of this compound class was driven by three factors: 1) to increase selectivity for anti-TB activity over human sEH activity, 2) to optimize PK profiles including solubility and 3) to maintain target inhibition. A new series of 1-adamantyl-3-heteroaryl ureas was designed and synthesized replacing the phenyl substituent of the original series with pyridines, pyrimidines, triazines, oxazoles, isoxazoles, oxadiazoles and pyrazoles. This study produced lead oxadiazole and pyrazole substituted adamantyl ureas with improved in vitro PK profiles, increased selectivity and good anti-TB potencies with sub µg/mL minimum inhibitory concentrations.
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影响因子：
3.5
作者：
Brown, Joshua R.;North, Elton J.;Hurdle, Julian G.;Morisseau, Christophe;Scarborough, Jerrod S.;Sun, Dianqing;Kordulakova, Jana;Scherman, Michael S.;Jones, Victoria;Grzegorzewicz, Anna;Crew, Rebecca M.;Jackson, Mary;McNeil, Michael R.;Lee, Richard E.
通讯作者：
Lee, Richard E.
影响因子：
5.6
作者：
Biswal, Bichitra K.;Morisseau, Christophe;James, Michael N. G.
通讯作者：
James, Michael N. G.
影响因子：
14.8
作者：
Grzegorzewicz, Anna E.;Ha Pham;Gundi, Vijay A. K. B.;Scherman, Michael S.;North, Elton J.;Hess, Tamara;Jones, Victoria;Gruppo, Veronica;Born, Sarah E. M.;Kordulakova, Jana;Chavadi, Sivagami Sundaram;Morisseau, Christophe;Lenaerts, Anne J.;Lee, Richard E.;McNeil, Michael R.;Jackson, Mary
通讯作者：
Jackson, Mary
影响因子：
3.8
作者：
Waters, Nigel J.;Jones, Rachel;Sohal, Bindi
通讯作者：
Sohal, Bindi
影响因子：
3.6
作者：
BORDWELL, FG;FRIED, HE;WHANG, YE
通讯作者：
WHANG, YE