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.

说明：该提案的长期目标是 是识别抗疟疾药物的结构特征 二螺-1，2，4，5-四氧杂环己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 为了实现这些目标，主要 研究者假设如下：i）口服生物利用度， 二螺-1，2，4，5-四氧杂环己烷是其代谢稳定性的函数，和 ii）桥连和氟取代的二螺-1，2，4，5-四氧杂环己烷可能具有 通过空间和电子途径抑制药物代谢 稳定，分别。 具体目标是： (1)合成并表征了八个桥联和五个氟取代的 二螺-1，2，4，5-四氧杂环己烷通过酸催化的过氧缩酮化的 合适的环己酮衍生物。 (2)测定二螺-1，2，4，5-四氧杂环己烷的代谢稳定性 具体目标（1）中所述的和对于十个二甲基和四甲基 二螺-1，2，4，5-四氧杂环己烷区域异构体（据说可从先前的 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-1，2，4，5-四氧杂环己烷， 体外抗恶性疟原虫内在抗疟活性。 (4)确定相对生物利用度的体内间接测量， 通过测量上述活性二螺-1，2，4，5-四氧杂环己烷的% 皮下和口服后寄生虫血症（感染后第6天） 分次给予64 mg/kg药物（天 3、4、5-感染后）。

项目成果

Characterization of chloroquine-hematin mu-oxo dimer binding by isothermal titration calorimetry.

通过等温滴定量热法表征氯喹-血红素 mu-氧二聚体结合。

• DOI: 10.1016/s0304-4165(00)00058-1
• 发表时间: 2000
• 期刊: Biochimica et biophysica acta
• 作者: Vippagunta,SR;Dorn,A;Ridley,RG;Vennerstrom,JL
• 通讯作者: Vennerstrom,JL

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

• DOI: 10.1021/jm9902180
• 发表时间: 1999-10
• 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

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。

• DOI: 10.1016/s0006-2952(99)00161-6
• 发表时间: 1999
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: Vippagunta,SR;Dorn,A;Bubendorf,A;Ridley,RG;Vennerstrom,JL
• 通讯作者: Vennerstrom,JL

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。

• DOI: 10.1021/jm0000766
• 发表时间: 2000
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Vennerstrom,JL;Dong,Y;Andersen,SL;AgerJr,AL;Fu,H;Miller,RE;Wesche,DL;Kyle,DE;Gerena,L;Walters,SM;Wood,JK;Edwards,G;Holme,AD;McLean,WG;Milhous,WK
• 通讯作者: Milhous,WK