期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 26, 期 2, 页码 355-360出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.12.003
关键词
Perforin; Perforin inhibitor; Diarylthiophene; Bioisostere; Immunosuppressant
资金
- Wellcome Trust [097767]
- Auckland Division of the Cancer Society of New Zealand
- Academy of Finland [135439]
- Orion-Farmos Research Foundation
- Academy of Finland (AKA) [135439, 135439] Funding Source: Academy of Finland (AKA)
Evolution from a furan-containing high-throughput screen (HTS) hit (1) resulted in isobenzofuran-1(3H)-one (2) as a potent inhibitor of the function of both isolated perforin protein and perforin delivered in situ by intact KHYG-1 NK cells. In the current study, structure-activity relationship (SAR) development towards a novel series of diarylthiophene analogues has continued through the use of substituted-benzene and -pyridyl moieties as bioisosteres for 2-thioxoimidazolidin-4-one (A) on a thiophene (B) -isobenzofuranone (C) scaffold. The resulting compounds were tested for their ability to inhibit perforin lytic activity in vitro. Carboxamide (23) shows a 4-fold increase over (2) in lytic activity against isolated perforin and provides good rationale for continued development within this class. (C) 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license.
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