Zhao, Chen published the artcileDesign of a New Histamine H3 Receptor Antagonist Chemotype: (3aR,6aR)-5-Alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrroles, Synthesis, and Structure-Activity Relationships, HPLC of Formula: 370880-09-4, the publication is Journal of Medicinal Chemistry (2009), 52(15), 4640-4649, database is CAplus and MEDLINE.
A new histamine H3 receptor (H3R) antagonist chemotype I (R1 = aryl, R2 = alkyl) was designed by combining key pharmacophoric elements from two different precursor structural series and then simplifying and optimizing the resulting combined structural features. First, analogs were made based on a previously identified conessine-based H3R antagonist series. While the first analogs II and 4b-epi-II showed no antagonistic activity to H3R, the mere addition of a key 4-cyanophenyl moiety, found in a reference compound (ABT-239), in place of the methoxyl group elevated the series to high potency at H3R. The resulting hybrid structure was judged too synthetically demanding to enable an extensive SAR study, thus forcing a strategy to simplify the chem. structure. The resulting (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrrole series proved to be highly potent, as exemplified by III having a human H3Ki of 0.54 nM, rat H3Ki of 4.57 nM, and excellent pharmacokinetics (PK) profile in rats (oral bioavailability of 39% and t1/2 of 2.4 h).
Journal of Medicinal Chemistry published new progress about 370880-09-4. 370880-09-4 belongs to esters-buliding-blocks, auxiliary class Other Aliphatic Heterocyclic,Chiral,Amide, name is (3aR,6aR)-tert-Butyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate, and the molecular formula is C8H15NO, HPLC of Formula: 370880-09-4.
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