ヘイヤ ブ ニ ブンプ スル カンシントウ ト カセン テイガイ フクリュウスイ ノ スイシツ トノ カンケイ ニツイテ : トットリケン ノ シュヨウカセン, ヒノガワ オヨビ チヨガワ ノ テイガイ シュスイ オ レイトシテ

We find an increasing demand for city water with the developments of social community and industry. It is possible that water resources can be obtained from fissure-structures in basements, and also from Alluvium and Diluvium strata. In the case that water resources are pumped up from Alluvial strata, we have sometimes perplexed problems as for the chemical properties of ground surface water with large contents of Fe2+, Mn3+ and so on. These phenomena will be owed to the existence of clay beds in reduced state. In this paper, the relationships between Alluvial clay beds and the chemical properties of groundsurface water in rivers will be discussed

Discovery of a Selective Kinase Inhibitor (TAK-632) Targeting Pan-RAF Inhibition: Design, Synthesis, and Biological Evaluation of <i>C</i>‑7-Substituted 1,3-Benzothiazole Derivatives

With the aim of discovering a selective kinase inhibitor targeting pan-RAF kinase inhibition, we designed novel 1,3-benzothiazole derivatives based on our thiazolo­[5,4-<i>b</i>]­pyridine class RAF/VEGFR2 inhibitor <b>1</b> and developed a regioselective cyclization methodology for the <i>C</i>-7-substituted 1,3-benzothiazole scaffold utilizing meta-substituted anilines. Eventually, we selected 7-cyano derivative <b>8B</b> (TAK-632) as a development candidate and confirmed its binding mode by cocrystal structure with BRAF. Accommodation of the 7-cyano group into the BRAF-selectivity pocket and the 3-(trifluoromethyl)­phenyl acetamide moiety into the hydrophobic back pocket of BRAF in the DFG-out conformation contributed to enhanced RAF potency and selectivity vs VEGFR2. Reflecting its potent pan-RAF inhibition and slow off-rate profile, <b>8B</b> demonstrated significant cellular activity against mutated <i>BRAF</i> or mutated <i>NRAS</i> cancer cell lines. Furthermore, in both A375 (<i>BRAF</i>^V600E) and HMVII (<i>NRAS</i>^Q61K) xenograft models in rats, <b>8B</b> demonstrated regressive antitumor efficacy by twice daily, 14-day repetitive administration without significant body weight loss

Design and Synthesis of Novel DFG-Out RAF/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Inhibitors. 1. Exploration of [5,6]-Fused Bicyclic Scaffolds

To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo­[1,2-<i>b</i>]­pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, <b>1</b>–<b>6</b>) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]­thiazolo­[5,4-<i>b</i>]­pyridine derivative <b>6d</b> showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of <b>6d</b> (<b>6d-SD</b>) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (<i>T</i>/<i>C</i> = −7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that <b>6d</b> is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity