METABOLIC STABILITY IN ANTIMALARIAL TETRAOXANES

抗疟四恶烷的代谢稳定性

• 批准号: 2076710
• 负责人: Jonathan L Vennerstrom
• 金额: $ 10.67万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2076710
• 关键词: Plasmodium; antimalarial agents; bridged cyclic compound; chemical substitution; cyclohexanones; drug design /synthesis /production; drug screening /evaluation; gas chromatography; halogenation; laboratory mouse; microorganism culture; microsomes; peroxides; pharmacokinetics

DESCRIPTION: It is stated that the long term objectives of this proposal are to identify structural features in antimalarial dispiro-1,2,4,5-tetraoxanes associated with high intrinsic antimalarial activity, metabolic stability, good oral bioavailability, and low neurotoxicity. To partially address these objectives, the principal investigator hypothesizes the following: i) oral bioavailability in dispiro-1,2,4,5-tetraoxanes is a function of their metabolic stability, and ii) bridged and fluoro-substituted dispiro-1,2,4,5-tetraoxanes might possess resistance to inactivating drug metabolism via steric and electronic stabilization, respectively. The specific aims are to: (1) Synthesize and characterize eight bridged and five fluoro-substituted dispiro-1,2,4,5-tetraoxanes via acid-catalyzed peroxyketalization of the appropriate cyclohexanone derivatives. (2) Determine metabolic stability for the dispiro-1,2,4,5-tetraoxanes described in specific aim (1) and for the ten dimethyl and tetramethyl dispiro-1,2,4,5-tetraoxane regioisomers (said to be available from previous work) in a liver microsome metabolic model using a quantitative GC assay. (3) Screen all of the dispiro-1,2,4,5-tetraoxanes described above for intrinsic antimalarial activity against Plasmodium falciparum in vitro. (4) Determine an in vivo indirect measure of relative bioavailability for active dispiro-1,2,4,5-tetraoxanes described above by measuring % parasitemia (day six-post infection) after both subcutaneous and oral administration of a divided dose of 64 mg/kg drug (days 3,4,5-post-infection) using Plasmodium berghei infection.

描述：据说该提案的长期目标 是为了识别抗疟药的结构特征 dispiro-1,2,4,5-四恶烷与高内在抗疟作用相关 活性、代谢稳定性、良好的口服生物利用度和低 神经毒性。 为了部分实现这些目标，主要 研究者假设如下： i) 口服生物利用度 dispiro-1,2,4,5-四恶烷是其代谢稳定性的函数，并且 ii) 桥联和氟取代的二螺-1,2,4,5-四恶烷可能具有 通过空间和电子对失活药物代谢的抵抗力 分别稳定。 具体目标是： (1) 八桥联和五氟取代的化合物的合成和表征 通过酸催化过氧缩酮化反应生成二螺-1,2,4,5-四恶烷 适当的环己酮衍生物。 (2) 测定二螺-1,2,4,5-四恶烷的代谢稳定性 具体目标 (1) 中描述的十个二甲基和四甲基 dispiro-1,2,4,5-四恶烷区域异构体（据说可以从以前的 工作）在肝微粒体代谢模型中使用定量 GC 测定。 (3) 筛选上述所有二螺-1,2,4,5-四恶烷 体外针对恶性疟原虫的内在抗疟活性。 (4) 确定体内相对生物利用度的间接测量 上述活性二螺-1,2,4,5-四恶烷通过测量% 皮下注射和口服后出现寄生虫血症（感染后第六天） 分次给药 64 mg/kg 药物（天 3、4、5-感染后）使用伯氏疟原虫感染。

项目成果

Synthesis and antimalarial activity of sixteen dispiro-1,2,4, 5-tetraoxanes: alkyl-substituted 7,8,15,16-tetraoxadispiro[5.2.5. 2]hexadecanes.

十六种二螺-1,2,4,5-四恶烷的合成和抗疟活性：烷基取代的7,8,15,16-四氧二螺[5.2.5。

• 发表时间: 2000-07-13
• 影响因子: 7.3
• 作者: Vennerstrom, J L;Dong, Y;Andersen, S L;Ager Jr, A L;Fu, H;Miller, R E;Wesche, D L;Kyle, D E;Gerena, L;Walters, S M;Wood, J K;Edwards, G;Holme, A D;McLean, W G;Milhous, W K
• 通讯作者: Milhous, W K

Deferoxamine: stimulation of hematin polymerization and antagonism of its inhibition by chloroquine.

去铁胺：刺激血红素聚合并拮抗氯喹对其的抑制作用。

• 发表时间: 1999-09-01
• 影响因子: 5.8
• 作者: Vippagunta, S R;Dorn, A;Bubendorf, A;Ridley, R G;Vennerstrom, J L
• 通讯作者: Vennerstrom, J L

Structural specificity of chloroquine-hematin binding related to inhibition of hematin polymerization and parasite growth.

氯喹-血红素结合的结构特异性与血红素聚合和寄生虫生长的抑制有关。

• DOI: 10.1021/jm9902180
• 发表时间: 1999-10-19
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: S. Vippagunta;A. Dorn;H. Matile;A. Bhattacharjee;J. Karle;W. Ellis;R. Ridley;J. Vennerstrom
• 通讯作者: J. Vennerstrom

Synthesis and antimalarial activity of 11 dispiro-1,2,4,5-tetraoxane analogues of WR 148999. 7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecanes substituted at the 1 and 10 positions with unsaturated and polar functional groups.

WR 148999 的 11 个二螺-1,2,4,5-四恶烷类似物的合成和抗疟活性。在 1 和 10 位被不饱和和极性官能团取代的 7,8,15,16-四氧二螺[5.2.5.2]十六烷

• DOI: 10.1021/jm980698f
• 发表时间: 1999-04-22
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Yuxiang Dong;H. Matile;J. Chollet;R. Kaminsky;James K. Wood;J. Vennerstrom
• 通讯作者: J. Vennerstrom

Short report: floxacrine analog WR 243251 inhibits hematin polymerization.

简短报告：氟沙克林类似物 WR 243251 抑制血红素聚合。

• 发表时间: 2001-07
• 作者: Dorn, A;Scovill, J P;Ellis, W Y;Matile, H;Ridley, R G;Vennerstrom, J L
• 通讯作者: Vennerstrom, J L