کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1376232 | 981952 | 2008 | 6 صفحه PDF | دانلود رایگان |
Spiro-isobenzofuranones 1a and 1b were discovered as potent, selective, and brain-penetrable non-imidazole H3 receptor inverse agonists. Our corporate sample collection was screened to identify 2a as a lead. Recognizing the right-hand portion of 2a as an essential pharmacophore, an extensive screen of the left-hand piperidine portion was carried out to yield the potent spiro-derivatives 2t−x. Spiro-isobenzofuranone 2x, the most potent among the derivatives, was converted to the corresponding amide 1a, which possessed dramatically improved H3 activity (IC50 = 0.72 nM; more than 20-fold improvement over 2x). Further elaboration led to the identification of 1b, a 5-methoxy derivative with an IC50 of 0.54 nM. Our studies demonstrated that derivatives 1a and 1b to be potent, selective, and brain-penetrable H3 inverse agonists.
Spiro-isobenzofuranones derivatives 1a and 1b were discovered as potent and selective H3 inverse agonists.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 18, Issue 18, 15 September 2008, Pages 5101–5106