- Systematic structure-activity relationship (SAR) exploration of diarylmethane backbone and discovery of a highly potent novel uric acid transporter 1 (URAT1) inhibitor
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In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (1a-1x and 1ha-1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200-and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0.035 μM against human URAT1 for 1h vs. 7.18 μM and 0.28 μM for lesinurad and benzbromarone, respectively). Compound 1h is the most potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the most potent ones currently under development in clinical trials. The present study demonstrates that the diarylmethane backbone represents a very promising molecular scaffold for the design of potent URAT1 inhibitors.
- Cai, Wenqing,Wu, Jingwei,Liu, Wei,Xie, Yafei,Liu, Yuqiang,Zhang, Shuo,Xu, Weiren,Tang, Lida,Wang, Jianwu,Zhao, Guilong
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- Synthesis and Biological Evaluation of 2-Aminobenzothiazole and Benzimidazole Analogs Based on the Clathrodin Structure
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A series of 2-aminobenzothiazole and benzimidazole analogs based on the clathrodin scaffold was synthesized and investigated for their antimicrobial and antiproliferative activities as well as for their effects in hepatitis C virus (HCV) replicon model. Compound 7, derived from 2-aminobenzothiazole, exhibited moderate antimicrobial activity only against the Gram-positive bacterium, Enterococcus faecalis. In the antiviral assay, compounds 4d and 7 were found to suppress the HCV replicon by >70%, but also to exhibit cytotoxicity against the host cells (35 and 44%, respectively). Compounds 4a and 7 demonstrated good activity in the antiproliferative assays on the human melanoma cell line A-375. To assess the selectivity of the effects between cancerous and noncancerous cells, a mouse fibroblast cell line was used. The IC50 values for compound 7 against the melanoma cell line A-375 and the fibroblast cell line BALB/c 3T3 were 16 and 71 μM, respectively, yielding fourfold selectivity toward the cancer cell line. These results suggest that compound 7 should be studied further in order to fully explore its potential for drug development. A series of novel 2-aminobenzothiazole and benzimidazole derivatives based on the clathrodin structure was synthesized and evaluated for antimicrobial, antiproliferative and antiviral activities. (9H-Fluoren-9-yl)-methyl [(2-aminobenzo[d]thiazol-6-yl)methyl]carbamate 7 exhibited antiproliferative activity against the melanoma cell line A-375 (IC50 = 16 μM) with 4-fold selectivity between cancerous (A-375) and noncancerous (BALB/c 3T3) cells.
- Montalv?o, Sofia,Leino, Teppo O.,Kiuru, Paula S.,Lillsunde, Katja-Emilia,Yli-Kauhaluoma, Jari,Tammela, P?ivi
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p. 137 - 149
(2016/02/09)
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- Piperidine derivative rennin inhibitors
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Disclosed are piperidine derivatives, their manufacture and use as inhibitors of renin.
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Page/Page column 18
(2010/02/08)
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