849659-38-7Relevant articles and documents
Discovery of novel, highly potent, and selective matrix metalloproteinase (MMP)-13 inhibitors with a 1,2,4-triazol-3-yl moiety as a zinc binding group using a structure-based design approach
Nara, Hiroshi,Kaieda, Akira,Sato, Kenjiro,Naito, Takako,Mototani, Hideyuki,Oki, Hideyuki,Yamamoto, Yoshio,Kuno, Haruhiko,Santou, Takashi,Kanzaki, Naoyuki,Terauchi, Jun,Uchikawa, Osamu,Kori, Masakuni
, p. 608 - 626 (2017/02/05)
On the basis of a superposition study of X-ray crystal structures of complexes of quinazoline derivative 1 and triazole derivative 2 with matrix metalloproteinase (MMP)-13 catalytic domain, a novel series of fused pyrimidine compounds which possess a 1,2,4-triazol-3-yl group as a zinc binding group (ZBG) was designed. Among the herein described and evaluated compounds, 31f exhibited excellent potency for MMP-13 (IC50 = 0.036 nM) and selectivities (greater than 1,500-fold) over other MMPs (MMP-1, -2, -3, -7, -8, -9, -10, and -14) and tumor necrosis factor-α converting enzyme (TACE). Furthermore, the inhibitor was shown to protect bovine nasal cartilage explants against degradation induced by interleukin-1 and oncostatin M. In this article, we report the discovery of extremely potent, highly selective, and orally bioavailable fused pyrimidine derivatives that possess a 1,2,4-triazol-3-yl group as a novel ZBG for selective MMP-13 inhibition.
Synthesis and structure-activity relationships of 2-amino-3-carboxy-4- phenylthiophenes as novel atypical protein kinase C inhibitors
Titchenell, Paul M.,Hollis Showalter,Pons, Jean-Fran?ois,Barber, Alistair J.,Jin, Yafei,Antonetti, David A.
supporting information, p. 3034 - 3038 (2013/06/27)
Recent evidence suggests atypical protein kinase C (aPKC) isoforms are required for both TNF- and VEGF-induced breakdown of the blood-retinal barrier (BRB) and endothelial permeability to 70 kDa dextran or albumin. A chemical library screen revealed a series of novel small molecule phenylthiophene based inhibitors of aPKC isoforms that effectively block permeability in cell culture and in vivo. In an effort to further elucidate the structural requirements of this series of inhibitors, we detail in this study a structure-activity relationship (SAR) built on screening hit 1, which expands on our initial pharmacophore model. The biological activity of our analogues was evaluated in models of bona fide aPKC-dependent signaling including NFκB driven-gene transcription as a marker for an inflammatory response and VEGF/TNF-induced vascular endothelial permeability. The EC50 for the most efficacious inhibitors (6, 32) was in the low nanomolar range in these two cellular assays. Our study demonstrates the key structural elements that confer inhibitory activity and highlights the requirement for electron-donating moieties off the C-4 aryl moiety of the 2-amino-3-carboxy-4-phenylthiophene backbone. These studies suggest that this class has potential for further development into small molecule aPKC inhibitors with therapeutic efficacy in a host of diseases involving increased vascular permeability and inflammation.
RETINOID-RELATED ORPHAN RECEPTOR GAMMA MODULATORS, COMPOSITION CONTAINING THEM AND USES THEREOF
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Page/Page column 35-36, (2012/08/08)
Provided are retinoid-related orphan receptor gamma(ROR γ) modulators of formula (I), processes for their preparation, pharmaceutical compositions containing them, and their uses in the treatment of diseases mediated by ROR γ.
