79128-78-2Relevant articles and documents
Novel, Self-Assembling Dimeric Inhibitors of Human β Tryptase
Giardina, Sarah F.,Werner, Douglas S.,Pingle, Maneesh,Feinberg, Philip B.,Foreman, Kenneth W.,Bergstrom, Donald E.,Arnold, Lee D.,Barany, Francis
, p. 3004 - 3027 (2020/04/17)
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 methyl 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 crystallography 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 chemistry to deliver bivalent drugs in a small molecule form.
A versatile approach for the synthesis of para -substituted arenes via palladium-catalyzed C-H functionalization and protodecarboxylation of benzoic acids
Pan, Shulei,Zhou, Bo,Zhang, Yanghui,Shao, Changdong,Shi, Guangfa
supporting information, p. 277 - 281 (2016/01/20)
While a great number of ortho C-H functionalization reactions have been developed and several breakthroughs have been achieved in meta C-H activation, para C-H functionalization is still in its infancy stage. In this article, a versatile strategy for the synthesis of para-substituted arenes has been developed via a tandem process consisting of palladium-catalyzed C-H functionalization and subsequent copper-catalyzed protodecarboxylation of benzoic acids. Both electron-withdrawing and electron-donating functionalities can be introduced into the para positions of arenes bearing a variety of substituents.
Design, synthesis and biological activity of selective and orally available TF/FVIIa complex inhibitors containing non-amidine P1 ligands
Miura, Masanori,Seki, Norio,Koike, Takanori,Ishihara, Tsukasa,Niimi, Tatsuya,Hirayama, Fukushi,Shigenaga, Takeshi,Sakai-Moritani, Yumiko,Tagawa, Ayako,Kawasaki, Tomihisa,Sakamoto, Shuichi,Okada, Minoru,Ohta, Mitsuaki,Tsukamoto, Shin-ichi
, p. 160 - 173 (2007/10/03)
We found the novel selective and orally available non-amidine TF/FVIIa complex inhibitor 21e, 4-({[(1S)-(aminocarbonyl)-3-methylbutyl]amino}carbonyl)-2′-({[4- (aminomethyl)phenyl]amino}carbonyl)-4′-(methylamino)biphenyl-2- carboxylic acid. The derivatives
