(3',4')-3-羟甲基-4-甲基-3',4'-二-(-)-樟脑酰基-(+)-凯拉内酯的前药设计、合成及药代动力学评价
Prodrug design, synthesis and pharmacokinetic evaluation of (3' , 4' )-3-hydroxymethyl-4-methyl-3',4'-di--()-camphanoyl-(+)--khellactone.
作者信息
Guo Huanfang, Zhuang Xiaomei, Qian Keduo, Sun Lianqi, Wang Xiaofeng, Li Hua, Lee Kuohsiung, Xie Lan
机构信息
Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
出版信息
Acta Pharm Sin B. 2012 Apr 1;2(2):213-219. doi: 10.1016/j.apsb.2012.02.008.
Abstract
3-Hydroxymethyl-4-methyl-DCK (, HMDCK) was discovered previously as a potent HIV non-nucleoside reverse transcriptase inhibitor (NNRTIs) (EC: 0.004 μM, TI: 6225) with a novel mechanism of action. It exerts anti-HIV activity by inhibiting the production of HIV-1 double-stranded viral DNA from a single-stranded DNA intermediate, rather than blocking the generation of single-stranded DNA from a RNA template, which is the mechanism of action of current HIV-1 RT inhibitors. However, the insufficient metabolic stability of limits its further clinical development. In the current study, a series of ester prodrugs of was designed and synthesized to explore the new drug candidates as NNRTIs. The l-alanine ester prodrug exhibited desirable pharmacokinetic properties and and showed improved oral bioavailability of 26% in rat, and would be a potential clinical candidate as a new anti-AIDS drug.
摘要
3-羟甲基-4-甲基-DCK（HMDCK）先前被发现是一种有效的HIV非核苷逆转录酶抑制剂（NNRTIs）（EC：0.004μM，TI：6225），具有新颖的作用机制。它通过抑制从单链DNA中间体产生HIV-1双链病毒DNA来发挥抗HIV活性，而不是像目前HIV-1 RT抑制剂的作用机制那样阻断从RNA模板产生单链DNA。然而，其代谢稳定性不足限制了它的进一步临床开发。在当前的研究中，设计并合成了一系列HMDCK的酯前药，以探索作为NNRTIs的新候选药物。L-丙氨酸酯前药表现出理想的药代动力学性质，在大鼠体内口服生物利用度提高了26%，将是一种潜在的新型抗艾滋病临床候选药物。
相似文献
1
Prodrug design, synthesis and pharmacokinetic evaluation of (3' , 4' )-3-hydroxymethyl-4-methyl-3',4'-di--()-camphanoyl-(+)--khellactone.(3',4')-3-羟甲基-4-甲基-3',4'-二-(-)-樟脑酰基-(+)-凯拉内酯的前药设计、合成及药代动力学评价
Acta Pharm Sin B. 2012 Apr 1;2(2):213-219. doi: 10.1016/j.apsb.2012.02.008.
2
Anti-AIDS agents. 52. Synthesis and anti-HIV activity of hydroxymethyl (3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone derivatives.抗艾滋病药物。52. 羟甲基(3'R,4'R)-3',4'-二-O-(S)-樟脑酰基-(+)-顺式凯刺内酯衍生物的合成及其抗HIV活性
J Med Chem. 2004 Jan 29;47(3):756-60. doi: 10.1021/jm030416y.
3
Computational studies and drug design for HIV-1 reverse transcriptase inhibitors of 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs.3',4'-二-O-(S)-樟脑酰基-(+)-顺式凯刺酮（DCK）类似物作为HIV-1逆转录酶抑制剂的计算研究与药物设计
J Comput Aided Mol Des. 2005 Apr;19(4):243-58. doi: 10.1007/s10822-005-4790-2.
4
Anti-AIDS agents. 60. Substituted 3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP) analogues as potent anti-HIV agents.抗艾滋病药物。60. 作为强效抗HIV药物的取代3'R,4'R-二-O-(-)-樟脑酰基-2',2'-二甲基二氢吡喃并[2,3-f]色酮（DCP）类似物。
J Med Chem. 2004 Jul 29;47(16):4072-82. doi: 10.1021/jm0400505.
5
Anti-AIDS agents. Part 47: Synthesis and anti-HIV activity of 3-substituted 3',4'-Di-O-(S)-camphanoyl-(3'R,4'R)-(+)-cis-khellactone derivatives.
Bioorg Med Chem Lett. 2001 Sep 3;11(17):2291-3. doi: 10.1016/s0960-894x(01)00437-1.
6
Anti-AIDS agents. 37. Synthesis and structure-activity relationships of (3'R,4'R)-(+)-cis-khellactone derivatives as novel potent anti-HIV agents.抗艾滋病药物。37. 新型强效抗HIV药物(3'R,4'R)-(+)-顺式凯刺酮衍生物的合成及其构效关系
J Med Chem. 1999 Jul 15;42(14):2662-72. doi: 10.1021/jm9900624.
7
Anti-AIDS agents 66: syntheses and anti-HIV activity of phenolic and aza 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) derivatives.抗艾滋病药物66：酚类和氮杂3',4'-二-O-（-）-樟脑酰基-（+）-顺式凯拉内酯（DCK）衍生物的合成及抗HIV活性
Bioorg Med Chem. 2007 Nov 1;15(21):6852-8. doi: 10.1016/j.bmc.2006.12.013. Epub 2006 Dec 13.
8
Anti-AIDS agents 84. Synthesis and anti-human immunodeficiency virus (HIV) activity of 2'-monomethyl-4-methyl- and 1'-thia-4-methyl-(3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs.抗艾滋病药物 84. 2'-单甲基-4-甲基-和 1'-硫代-4-甲基-(3'R,4'R)-3',4'-二-O-(S)-樟脑酰基-(+)-顺式金合欢内酯 (DCK)类似物的合成及抗人类免疫缺陷病毒 (HIV)活性。
Bioorg Med Chem. 2010 Oct 15;18(20):7203-11. doi: 10.1016/j.bmc.2010.08.031. Epub 2010 Aug 19.
9
Anti-AIDS agents. Part 62: anti-HIV activity of 2'-substituted 4-methyl-3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (4-methyl DCK) analogs.抗艾滋病药物。第62部分：2'-取代的4-甲基-3',4'-二-O-（-）-樟脑酰基-（+）-顺式凯拉内酯（4-甲基DCK）类似物的抗HIV活性。
Bioorg Med Chem Lett. 2004 Dec 6;14(23):5855-7. doi: 10.1016/j.bmcl.2004.09.032.
10
Anti-AIDS agents 82: synthesis of seco-(3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives as novel anti-HIV agents.抗艾滋病药物 82：新型抗 HIV 药物（S）-樟酰基-(+)-顺式金莲花内酯（DCK）衍生物的全合成。
Bioorg Med Chem. 2010 Jun 15;18(12):4363-73. doi: 10.1016/j.bmc.2010.04.089. Epub 2010 Apr 29.
引用本文的文献
1
Drug/Lead Compound Hydroxymethylation as a Simple Approach to Enhance Pharmacodynamic and Pharmacokinetic Properties.药物/先导化合物羟甲基化：一种增强药效学和药代动力学性质的简单方法
Front Chem. 2022 Feb 14;9:734983. doi: 10.3389/fchem.2021.734983. eCollection 2021.
2
Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene[3,2-]pyrimidine derivatives as potent HIV-1 NNRTIs.探索NNIBP的疏水通道导致发现了新型哌啶取代的噻吩并[3,2 -]嘧啶衍生物，作为有效的HIV-1非核苷类逆转录酶抑制剂。
Acta Pharm Sin B. 2020 May;10(5):878-894. doi: 10.1016/j.apsb.2019.08.013. Epub 2019 Sep 14.
3
Advanced Prodrug Strategies in Nucleoside and Non-Nucleoside Antiviral Agents: A Review of the Recent Five Years.核苷类和非核苷类抗病毒药物的高级前药策略：对最近五年的综述。
Molecules. 2017 Oct 16;22(10):1736. doi: 10.3390/molecules22101736.
4
Pharmacokinetic and Metabolic Characteristics of Herb-Derived Khellactone Derivatives, A Class of Anti-HIV and Anti-Hypertensive: A Review.一类具有抗HIV和抗高血压作用的草本来源凯林内酯衍生物的药代动力学和代谢特征：综述
Molecules. 2016 Mar 8;21(3):314. doi: 10.3390/molecules21030314.
本文引用的文献
1
Anti-AIDS agents 65: investigation of the in vitro oxidative metabolism of 3',4'-Di-O-(-)-camphanoyl-(+)-cis-khellactone derivatives as potent anti-hiv agents.
Drug Metab Dispos. 2005 Nov;33(11):1588-92. doi: 10.1124/dmd.105.004218. Epub 2005 Aug 8.
2
Mechanism of action and resistant profile of anti-HIV-1 coumarin derivatives.抗HIV-1香豆素衍生物的作用机制及耐药情况
Virology. 2005 Feb 20;332(2):623-8. doi: 10.1016/j.virol.2004.11.033.
3
Anti-AIDS agents. 52. Synthesis and anti-HIV activity of hydroxymethyl (3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone derivatives.抗艾滋病药物。52. 羟甲基(3'R,4'R)-3',4'-二-O-(S)-樟脑酰基-(+)-顺式凯刺内酯衍生物的合成及其抗HIV活性
J Med Chem. 2004 Jan 29;47(3):756-60. doi: 10.1021/jm030416y.
4
Anti-AIDS agents. 42. Synthesis and anti-HIV activity of disubstituted (3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone analogues.抗艾滋病药物。42. 二取代(3'R,4'R)-3',4'-二-O-(S)-樟脑酰基-(+)-顺式凯刺内酯类似物的合成及抗HIV活性
J Med Chem. 2001 Mar 1;44(5):664-71. doi: 10.1021/jm000070g.
5
Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2.更昔洛韦前体药物缬更昔洛韦通过肽转运体PEPT1和PEPT2的转运。
J Pharm Sci. 2000 Jun;89(6):781-9. doi: 10.1002/(SICI)1520-6017(200006)89:6<781::AID-JPS10>3.0.CO;2-7.
6
Anti-AIDS agents. 37. Synthesis and structure-activity relationships of (3'R,4'R)-(+)-cis-khellactone derivatives as novel potent anti-HIV agents.抗艾滋病药物。37. 新型强效抗HIV药物(3'R,4'R)-(+)-顺式凯刺酮衍生物的合成及其构效关系
J Med Chem. 1999 Jul 15;42(14):2662-72. doi: 10.1021/jm9900624.
7
The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data.从临床前和体外代谢数据预测人体药代动力学参数。
J Pharmacol Exp Ther. 1997 Oct;283(1):46-58.
8
Metabolism of dopamine prodrug, docarpamine.
Hypertens Res. 1995 Jun;18 Suppl 1:S211-3. doi: 10.1291/hypres.18.supplementi_s211.
9
Anti-AIDS agents. 15. Synthesis and anti-HIV activity of dihydroseselins and related analogs.抗艾滋病药物。15. 二氢水芹素及其相关类似物的合成与抗HIV活性
J Med Chem. 1994 Nov 11;37(23):3947-55. doi: 10.1021/jm00049a014.
Zotero 插件