Giardina, Sarah F. published the artcileNovel, Self-Assembling Dimeric Inhibitors of Human β Tryptase, SDS of cas: 918331-73-4, the publication is Journal of Medicinal Chemistry (2020), 63(6), 3004-3027, database is CAplus and MEDLINE.
β-Tryptase, a homotetrameric serine protease, has four identical active sites facing a central pore, presenting an optimized setting for the rational design of bivalent inhibitors that bridge two adjacent sites. Using diol, hydroxymethyl phenols or benzoyl Me hydroxamates, and boronic acid chemistries to reversibly join two [3-(1-acylpiperidin-4-yl)phenyl]methanamine core ligands, we have successfully produced a series of self-assembling heterodimeric inhibitors. These heterodimeric tryptase inhibitors demonstrate superior activity compared to monomeric modes of inhibition. X-ray crystallog. validated the dimeric mechanism of inhibition, and compounds demonstrated high selectivity against related proteases, good target engagement, and tryptase inhibition in HMC1 xenograft models. Screening 3872 possible combinations from 44 boronic acid and 88 diol derivatives revealed several combinations that produced nanomolar inhibition, and seven unique pairs produced greater than 100-fold improvement in potency over monomeric inhibition. These heterodimeric tryptase inhibitors demonstrate the power of target-driven combinatorial chem. to deliver bivalent drugs in a small mol. form.
Journal of Medicinal Chemistry published new progress about 918331-73-4. 918331-73-4 belongs to chlorides-buliding-blocks, auxiliary class Chloride,Boronic acid and ester,Carboxylic acid,Benzene,Boronate Esters,Boronic Acids,Boronic acid and ester,Boronate Esters, name is 4-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and the molecular formula is C13H16BClO4, SDS of cas: 918331-73-4.
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