On October 1, 2018, Shinozuka, Tsuyoshi; Tsukada, Tomoharu; Fujii, Kunihiko; Tokumaru, Eri; Shimada, Kousei; Onishi, Yoshiyuki; Matsui, Yumi; Wakimoto, Satoko; Kuroha, Masanori; Ogata, Tsuneaki; Araki, Kazushi; Ohsumi, Jun; Sawamura, Ryoko; Watanabe, Nobuaki; Yamamoto, Hideki; Fujimoto, Kazunori; Tani, Yoshiro; Mori, Makoto; Tanaka, Jun published an article.Safety of 4-Chloro-2,6-difluoropyridine The title of the article was Discovery of DS-6930, a potent selective PPARγ modulator. Part II: Lead optimization. And the article contained the following:
Attempts were made to reduce the lipophilicity of previously synthesized compound (II) for the avoidance of hepatotoxicity. The replacement of the left-hand side benzene with 2-pyridine resulted in the substantial loss of potency. Because poor membrane permeability was responsible for poor potency in vitro, the adjustment of lipophilicity was examined, which resulted in the discovery of di-Me pyridine derivative (I, DS-6930). In preclin. studies, DS-6930 demonstrated high PPARγ agonist potency with robust plasma glucose reduction DS-6930 maintained diminished PPARγ-related adverse effects upon toxicol. evaluation in vivo, and demonstrated no hepatotoxicity. Cofactor recruitment assay showed that several cofactors, such as RIP140 and PGC1, were significantly recruited, whereas several canonical factors was not affected. This selective cofactor recruitment was caused due to the distinct binding mode of DS-6930. The calcium salt, DS-6930b, which is expected to be an effective inducer of insulin sensitization without edema, could be evaluated clin. in T2DM patients. The experimental process involved the reaction of 4-Chloro-2,6-difluoropyridine(cas: 34968-33-7).Safety of 4-Chloro-2,6-difluoropyridine
The Article related to ds 6930 preparation ppar modulator diabetes, benzimidazole, ds-6930, pparγ, Pharmacology: Structure-Activity and other aspects.Safety of 4-Chloro-2,6-difluoropyridine