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设计、合成及功能化四氢-β-咔啉衍生物的构效关系作为新型 PDE5 抑制剂。

Design, synthesis and structure-activity relationship of functionalized tetrahydro-β-carboline derivatives as novel PDE5 inhibitors.

机构信息

Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.

出版信息

Arch Pharm (Weinheim). 2011 Mar;344(3):149-57. doi: 10.1002/ardp.201000236. Epub 2010 Dec 22.

DOI:10.1002/ardp.201000236
PMID:21384413
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4980839/
Abstract

Starting from tadalafil as a template, a series of functionalized tetrahydro-β-carboline derivatives have been prepared and identified as novel potent and selective PDE5 inhibitors. Replacing the 3,4-methylenedioxyphenyl at position 6 of tadalafil, together with elongation of the N2-methyl substituent and manipulation of the stereochemical aspects of the two chiral carbons led to the identification of compound XXI, a highly potent PDE5 inhibitor (IC(50)  = 3 nM). Compound XXI was also highly selective for PDE5 versus PDE3B, PDE4B, and PDE11A, with a selectivity index of 52 and 235 towards PDE5 rather than PDE11 with both cAMP and cGMP as substrate, respectively.

摘要

以他达拉非为模板，我们合成了一系列的四氢-β-咔啉衍生物，并将其鉴定为新型强效和选择性 PDE5 抑制剂。将他达拉非 6 位的 3,4-亚甲二氧基苯基替换，同时延长 N2-甲基取代基，并调整两个手性碳原子的立体化学方面，得到了化合物 XXI，这是一种高效的 PDE5 抑制剂（IC50=3 nM）。化合物 XXI 对 PDE5 的选择性也高于 PDE3B、PDE4B 和 PDE11A，分别以 cAMP 和 cGMP 为底物时，对 PDE5 的选择性指数为 52 和 235，而对 PDE11 的选择性指数分别为 52 和 235。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e01/4980839/345fcb4c3689/nihms-800110-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e01/4980839/19ced9deac17/nihms-800110-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e01/4980839/527cdaaceb17/nihms-800110-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e01/4980839/04736fa95f86/nihms-800110-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e01/4980839/84d1d52108df/nihms-800110-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e01/4980839/06e5b901bf08/nihms-800110-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e01/4980839/345fcb4c3689/nihms-800110-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e01/4980839/19ced9deac17/nihms-800110-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e01/4980839/527cdaaceb17/nihms-800110-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e01/4980839/04736fa95f86/nihms-800110-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e01/4980839/84d1d52108df/nihms-800110-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e01/4980839/06e5b901bf08/nihms-800110-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e01/4980839/345fcb4c3689/nihms-800110-f0002.jpg

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2
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Brain Res. 2006 Nov 6;1118(1):192-8. doi: 10.1016/j.brainres.2006.08.028. Epub 2006 Sep 7.
3
[Phosphodiesterase inhibitors: effectiveness and new applications].
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Chin Med. 2022 Dec 31;17(1):147. doi: 10.1186/s13020-022-00705-5.
4
Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile.基于二酮哌嗪的柔性他达那非类似物：合成、晶体结构和生物学活性特征。
Molecules. 2021 Feb 3;26(4):794. doi: 10.3390/molecules26040794.
5
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Aging (Albany NY). 2020 May 23;12(10):9621-9632. doi: 10.18632/aging.103232.
6
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8
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Molecules. 2014 Jan 27;19(2):1544-67. doi: 10.3390/molecules19021544.
9
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Curr Colorectal Cancer Rep. 2012 Dec;8(4):325-330. doi: 10.1007/s11888-012-0142-5.
10
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[磷酸二酯酶抑制剂：疗效与新应用]
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4
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Int J Impot Res. 2005 Sep-Oct;17(5):467-8. doi: 10.1038/sj.ijir.3901377.
5
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Int J Impot Res. 2005 Jan-Feb;17(1):5-9. doi: 10.1038/sj.ijir.3901283.
6
Suppression of cyclic GMP-specific phosphodiesterase 5 promotes apoptosis and inhibits growth in HT29 cells.环磷酸鸟苷特异性磷酸二酯酶5的抑制促进HT29细胞凋亡并抑制其生长。
J Cell Biochem. 2005 Feb 1;94(2):336-50. doi: 10.1002/jcb.20286.
7
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8
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9
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Circ Res. 2003 Aug 22;93(4):280-91. doi: 10.1161/01.RES.0000087541.15600.2B.
10
A fluorescence polarization assay for cyclic nucleotide phosphodiesterases.一种用于环核苷酸磷酸二酯酶的荧光偏振测定法。
J Biomol Screen. 2002 Jun;7(3):215-22. doi: 10.1177/108705710200700305.