13433-48-2Relevant academic research and scientific papers
Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent
Zhang, Xianglei,Dong, Guangyu,Li, Heng,Chen, Wuyan,Li, Jian,Feng, Chunlan,Gu, Zhanni,Zhu, Fenghua,Zhang, Rui,Li, Minjun,Tang, Wei,Liu, Hong,Xu, Yechun
, p. 5579 - 5593 (2019)
Psoriasis is a common, chronic inflammatory disease characterized by abnormal skin plaques, and the effectiveness of phosphodiesterase 4 (PDE4) inhibitor to lessen the symptoms of psoriasis has been proved. Aiming to find a novel PDE4 inhibitor acting as an effective, safe, and convenient therapeutic agent, we constructed a library consisting of berberine analogues, and compound 2 with a tetrahydroisoquinoline scaffold was identified as a novel and potent hit. The structure-aided and cell-based structure-activity relationship studies on a series of tetrahydro-isoquinolines lead to efficient discovery of a qualified lead compound (16) with the high potency and selectivity, well-characterized binding mechanism, high cell permeability, good safety and pharmacokinetic profile, and impressive in vivo efficacy on antipsoriasis, in particular with a topical application. Thus, our study presents a prime example for efficient discovery of novel, potent lead compounds derived from natural products using a combination of medicinal chemistry, biochemical, biophysical, and pharmacological approaches.
Design, synthesis, and biological evaluation of tetrahydroisoquinolines derivatives as novel, selective PDE4 inhibitors for antipsoriasis treatment
Zhang, Rui,Li, Heng,Zhang, Xianglei,Li, Jian,Su, Haixia,Lu, Qiukai,Dong, Guangyu,Dou, Huixia,Fan, Chen,Gu, Zhanni,Mu, Qianwen,Tang, Wei,Xu, Yechun,Liu, Hong
supporting information, (2020/11/24)
Psoriasis is a kind of chronic inflammatory skin disorder, while the long-term use of conventional therapies for this disease are limited by severe adverse effects. Novel small molecules associated with new therapeutic mechanisms are greatly needed. It is known that phosphodiesterase 4 (PDE4) plays a central role in regulating inflammatory responses through hydrolyzing intracellular cyclic adenosine monophosphate (cAMP), making PDE4 to be an important target for the treatment of inflammatory diseases (e.g. psoriasis). In our previous work, we identified a series of novel PDE4 inhibitors with a tetrahydroisoquinoline scaffold through structure-based drug design, among which compound 1 showed moderate inhibition activity against PDE4. In this study, a series of novel tetrahydroisoquinoline derivatives were developed based on the crystal structure of PDE4D in complex with compound 1. Anti-inflammatory effects of these compounds were evaluated, and compound 36, with high safety, permeability and selectivity, exhibited significant inhibitory potency against the enzymatic activity of PDE4D and the TNF-α release from the LPS-stimulated RAW 264.7 and hPBMCs. Moreover, an in vivo study demonstrated that a topical administration of 36 achieved more significant efficacy than calcipotriol to improve the features of psoriasis-like skin inflammation. Overall, our study provides a basis for further development of tetrahydroisoquinoline-based PDE4 inhibitors against psoriasis.
Design, Synthesis, and Biological Evaluation of Novel Tetrahydroprotoberberine Derivatives (THPBs) as Selective α1A-Adrenoceptor Antagonists
Guo, Diliang,Li, Jing,Lin, Henry,Zhou, Yu,Chen, Ying,Zhao, Fei,Sun, Haifeng,Zhang, Dan,Li, Honglin,Shoichet, Brian K.,Shan, Lei,Zhang, Weidong,Xie, Xin,Jiang, Hualiang,Liu, Hong
, p. 9489 - 9502 (2016/11/11)
A novel series of tetrahydroprotoberberine derivatives (THPBs) were designed, synthesized, and evaluated as selective α1A-adrenergic receptors (AR) antagonists for the treatment of benign prostatic hyperplasia. On the basis of the pharmacophore model of the marketed drug silodosin, THPBs were modified by introducing an indole segment into their core scaffolds. In calcium assays, 7 out of 32 compounds displayed excellent antagonistic activities against α1A-ARs, with IC50 less than 250 nM. Among them, compound (S)-27 had the most potent biological activity; its IC50 toward α1A-AR was 12.8 ± 2.2 nM, which is 781 and 20 times more selective than that toward α1B- and α1D-AR, respectively. In the functional assay using isolated rat tissues, compound (S)-27 inhibited norepinephrine-induced urethra smooth muscle contraction potently (IC50 = 0.5 ± 0.3 nM), without inhibiting the aortic contraction (IC50 > 1000 nM), displaying a better tissue selectivity than the marketed drug silodosin. Additional results of preliminary safety studies (acute toxicity and hERG inhibition) and pharmacokinetics studies indicated the potential druggability for compound (S)-27 which is a promising lead for the development of selective α1A-AR antagonists for the treatment of BPH.
Structural optimization of berberine as a synergist to restore antifungal activity of fluconazole against drug-resistant Candida albicans
Liu, Hong,Wang, Liang,Li, Yan,Liu, Jiang,An, Maomao,Zhu, Shaolong,Cao, Yongbing,Jiang, Zhihui,Zhao, Mingzhu,Cai, Zhan,Dai, Li,Ni, Tingjunhong,Liu, Wei,Chen, Simin,Wei, Changqing,Zang, Chengxu,Tian, Shujuan,Yang, Jingyu,Wu, Chunfu,Zhang, Dazhi,Liu, Hua,Jiang, Yuanying
supporting information, p. 207 - 216 (2014/01/17)
We have conducted systematic structural modification, deconstruction, and reconstruction of the berberine core with the aim of lowering its cytotoxicity, investigating its pharmacophore, and ultimately, seeking novel synergistic agents to restore the effectiveness of fluconazole against fluconazole-resistant Candida albicans. A structure-activity relationship study of 95 analogues led us to identify the novel scaffold of N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-2- (substituted phenyl)acetamides 7 a-l, which exhibited remarkable levels of in vitro synergistic antifungal activity. Compound 7 d (N-(2-(benzo[d][1,3]dioxol- 5-yl)ethyl)-2-(2-fluorophenyl)acetamide) significantly decreased the MIC 80 values of fluconazole from 128.0 μg mL-1 to 0.5 μg mL-1 against fluconazole-resistant C. albicans and exhibited much lower levels of cytotoxicity than berberine toward human umbilical vein endothelial cells. Build it better: Structural optimization of berberine led to the identification of the novel scaffold of N-(2-(benzo[d][1,3]dioxol-5-yl) ethyl)-2-(substituted phenyl)acetamides 7 a-l, which exhibited remarkable in vitro synergistic antifungal activity against fluconazole-resistant Candida albicans in combination with fluconazole. Compound 7 d exhibited much lower cytotoxicity than berberine toward human umbilical vein endothelial cells. Copyright
Antiinflammatory and antiproteolytic activities of newer indolyl isoquinolines
Tandon,Tandon,Barthwal,Bhalla,Bhargava
, p. 1233 - 1235 (2007/10/02)
Several indolyl isoquinoline derivatives were synthesized and evaluated for their antiinflammatory and antiproteolytic activities. These derivatives possessed 9.2-32.4% inhibition at a dose of 100 mg/kg i.p. against carrageenin-induced oedema. Four of the
