Subrath Joan, Wang Daniel, Wu Biqi, Niu Chuansheng, Boschelli Diane H, Lee Julie, Yang Xiaoke, Brennan Agnes, Chaudhary Divya
Wyeth Research, Chemical Sciences, 401 N. Middletown Road, Pearl River, NY 10965, United States.
Bioorg Med Chem Lett. 2009 Sep 15;19(18):5423-5. doi: 10.1016/j.bmcl.2009.07.109. Epub 2009 Jul 26.
We earlier reported that 3-pyridinecarbonitriiles with a 4-methylindolyl-5-amino group at C-4 and a phenyl group at C-5 were inhibitors of PKCtheta. Keeping the group at C-4 of the pyridine core constant, we varied the water solubilizing group on the phenyl ring at C-5 and then replaced the C-5 phenyl ring with several monocyclic heteroaryl rings, including furan, thiophene and pyridine. Analog 6e with a 4-methylindol-5-ylamino group at C-4 and a 5-[(4-methylpiperazin-1-yl)methyl]-2-furyl group C-5 had an IC50 value of 4.5 nM for the inhibition of PKCtheta.
我们之前报道过，在C-4位带有4-甲基吲哚基-5-氨基且在C-5位带有苯基的3-吡啶甲腈是蛋白激酶Cθ（PKCθ）的抑制剂。保持吡啶核心C-4位的基团不变，我们改变了C-5位苯环上的水溶性基团，然后用几个单环杂芳基环取代C-5位的苯环，包括呋喃、噻吩和吡啶。在C-4位带有4-甲基吲哚-5-基氨基且在C-5位带有5-[(4-甲基哌嗪-1-基)甲基]-2-呋喃基的类似物6e对PKCθ抑制作用的IC50值为4.5 nM。
