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  • Title: Synthesis and evaluation of a spiro-isobenzofuranone class of histamine H3 receptor inverse agonists.
    Author: Jitsuoka M, Tsukahara D, Ito S, Tanaka T, Takenaga N, Tokita S, Sato N.
    Journal: Bioorg Med Chem Lett; 2008 Sep 15; 18(18):5101-6. PubMed ID: 18768318.
    Abstract:
    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 (IC(50)=0.72 nM; more than 20-fold improvement over 2x). Further elaboration led to the identification of 1b, a 5-methoxy derivative with an IC(50) of 0.54 nM. Our studies demonstrated that derivatives 1a and 1b to be potent, selective, and brain-penetrable H3 inverse agonists.
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