13433-48-2Relevant articles and documents
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 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.
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
