Design and Synthesis Studies of α-Methylene-γ-butyrolactones Antagonists of GPR52

doi:10.6023/cjoc202303005

Chinese Journal of Organic Chemistry ›› 2023, Vol. 43 ›› Issue (11): 3916-3929.DOI: 10.6023/cjoc202303005 Previous Articles Next Articles

α-亚甲基-γ-丁内酯类GPR52拮抗剂的设计与合成研究

沈冬杭^a^,^b^,^c†, 李鑫^a^,^b†, 郭世猛^a^,^b, 谢欣^a^,^b^,^c^,^*(), 南发俊^a^,^b^,^c^,^*()

a 中国科学院大学北京 100049
b 中国科学院上海药物研究所上海 201203
c 杭州高等研究院杭州 310024

收稿日期:2023-03-02 修回日期:2023-05-25 发布日期:2023-07-05
作者简介:
†共同第一作者

Design and Synthesis Studies of α-Methylene-γ-butyrolactones Antagonists of GPR52

Donghang Shen^a^,^b^,^c†, Xin Li^a^,^b†, Shimeng Guo^a^,^b, Xin Xie^a^,^b^,^c(), Fajun Nan^a^,^b^,^c()

a University of Chinese Academy of Sciences, Beijing 100049
b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
c Hangzhou Institute for Advanced Study, Hangzhou 310024

Received:2023-03-02 Revised:2023-05-25 Published:2023-07-05
Contact: * E-mail: fjnan@simm.ac.cn; xxie@simm.ac.cn
About author:
†These authors contributed equally to this work.

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Abstract

GPR52 is an orphan G protein-coupled receptor, which is highly expressed in the striatum and associated with Huntingdon’s disease (HD), a neurodegenerative disease. HD is caused by the accumulation of mutant Huntingdon’s protein (mHTT). Reduction of mHTT level by inhibition of GPR52 is a novel potential method of HD therapy. Through high throughput screening, the natural product E7 was found as a covalent antagonist against GPR52 (IC₅₀=12.0 μmol/L). In this study, the structure of E7 was simplified and the α-methylene-γ-butyrolactone moiety was retained. And 34 novel α-methylene-γ-butyro- lactone derivatives were designed and synthesized, of which (±)-((2S,3R)-4-methylene-5-oxo-2-(thiophen-2-yl)-tetrahydro- furan-3-yl)methyl 4-methoxybenzoate (10m) showed most potent antagonistic activity against GPR52 (IC₅₀=0.58 μmol/L). Meanwhile, the structure-activity relationship was determined preliminarily and the necessary of α-methylene-γ- butyrolactone moiety was verified.

Key words: Huntingdon’s disease, G protein-coupled receptor, GPR52, α-methylene-γ-butyrolactones, antagonist

Cite this article

Donghang Shen, Xin Li, Shimeng Guo, Xin Xie, Fajun Nan. Design and Synthesis Studies of α-Methylene-γ-butyrolactones Antagonists of GPR52[J]. Chinese Journal of Organic Chemistry, 2023, 43(11): 3916-3929.

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Fig. & Tab. 9

References 17

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Compd.	IC₅₀/(μmol•L^–1)	Compd.	IC₅₀/(μmol•L^–1)
7a	1.73±0.09	8a	3.77±0.15
7b	0.67±0.18	8b	2.20±0.35
7c	3.99±0.35	8c	1.55±0.22
7d	1.53±0.22	8d	3.95±0.31
E7	11.89

Compd.	IC₅₀/(μmol•L^–1)	Compd.	IC₅₀/(μmol•L^–1)
7a	1.73±0.09	8a	3.77±0.15
7b	0.67±0.18	8b	2.20±0.35
7c	3.99±0.35	8c	1.55±0.22
7d	1.53±0.22	8d	3.95±0.31
E7	11.89

Compd.	IC₅₀/(μmol•L^–1)	Compd.	R³	IC₅₀/(μmol•L^–1)
7b	0.67±0.18	10m		0.58±0.09
10a	20.8±2.4	10n		3.79±0.82
10b	19.5±3.3	10o		2.02±0.48
10c	6.50±0.91	10p		3.75±0.29
10d	10.4±1.8	10q		4.55±1.20
10e	3.54±0.92	10r		1.33±0.22
10f	4.00±1.1	10s		1.44±0.20
10g	1.44±0.21	10t		4.85±0.59
10h	1.66±0.42	10u		2.43±0.09
10i	2.35±0.17	10v		5.15±0.31
10j	5.33±0.63	10w		3.76±1.10
10k	4.72±0.28	10x		8.59±1.00
10l	5.03±0.26	E7	—	11.89

Compd.	IC₅₀/(μmol•L^–1)	Compd.	R³	IC₅₀/(μmol•L^–1)
7b	0.67±0.18	10m		0.58±0.09
10a	20.8±2.4	10n		3.79±0.82
10b	19.5±3.3	10o		2.02±0.48
10c	6.50±0.91	10p		3.75±0.29
10d	10.4±1.8	10q		4.55±1.20
10e	3.54±0.92	10r		1.33±0.22
10f	4.00±1.1	10s		1.44±0.20
10g	1.44±0.21	10t		4.85±0.59
10h	1.66±0.42	10u		2.43±0.09
10i	2.35±0.17	10v		5.15±0.31
10j	5.33±0.63	10w		3.76±1.10
10k	4.72±0.28	10x		8.59±1.00
10l	5.03±0.26	E7	—	11.89

Comp.	X	R³	IC₅₀/(μmol•L^–1)
7b			0.67±0.18
12a			NA
10m			0.58±0.09
12b			NA

α-亚甲基-γ-丁内酯类GPR52拮抗剂的设计与合成研究

Design and Synthesis Studies of α-Methylene-γ-butyrolactones Antagonists of GPR52

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References 17

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Compd.	IC₅₀/(μmol•L^–1)
Compd.	GPR52	β2AR	GLP-1R	GHSR
Propranolol	—	0.057	—	—
Exendin (9-39)	—	—	0.136	—
Substance P	—	—	—	0.458
7b	0.67±0.18	>100	>100	>100
10m	0.58±0.09	>100	>100	>10

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Compd.	R⁴	IC₅₀/(μmol•L^–1)
10m		0.58±0.09
6b		>30
13		5.09±0.78
19		15.9±1.6

Compd.	R⁴	IC₅₀/(μmol•L^–1)
10m		0.58±0.09
6b		>30
13		5.09±0.78
19		15.9±1.6