血小板衍生生长因子受体自身磷酸化新型抑制剂对系膜增生性肾小球肾炎大鼠的有益作用。

Beneficial effects of a novel inhibitor of platelet-derived growth factor receptor autophosphorylation in the rat with mesangial proliferative glomerulonephritis.

Yagi M, Kato S, Kobayashi Y, Kobayashi N, Iinuma N, Nakamura K, Kubo K, Ohyama S I, Murooka H, Shimizu T, Nishitoba T, Osawa T, Nagano N

Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan.

Gen Pharmacol. 1998 Nov;31(5):765-73. doi: 10.1016/s0306-3623(98)00104-9.

Abstract

Our original compound, Ki6896 ((4-t-butylphenyl)(4-[(6,7-dimethoxy-4-quinolyl) oxy]phenyl) methanone) strongly inhibited the autophosphorylation of platelet-derived growth factor (PDGF) beta-receptor (IC50=0.31 microM) and that of basic fibroblast growth factor receptor (IC50=3.1 microM), whereas it did not inhibit some other kinases. 2. The [3H]thymidine incorporation and the growth of mesangial cells under the stimulation of PDGF were inhibited by Ki6896 in a dose-dependent manner. 3. In the mesangial proliferative glomerulonephritis rats induced by anti-Thy-1 monoclonal antibody, glomerulosclerosis was ameliorated and the number of glomerular proliferating cells was decreased by the daily administration of Ki6896. However, the accumulation of type I collagen and fibronectin in the glomeruli was not suppressed by Ki6896.

摘要

我们最初的化合物Ki6896（(4-叔丁基苯基)(4-[(6,7-二甲氧基-4-喹啉基)氧基]苯基)甲酮）强烈抑制血小板衍生生长因子（PDGF）β受体的自磷酸化（IC50 = 0.31微摩尔）和碱性成纤维细胞生长因子受体的自磷酸化（IC50 = 3.1微摩尔），而它不抑制其他一些激酶。2. Ki6896以剂量依赖性方式抑制PDGF刺激下系膜细胞的[3H]胸苷掺入和生长。3. 在抗Thy-1单克隆抗体诱导的系膜增生性肾小球肾炎大鼠中，每日给予Ki6896可改善肾小球硬化并减少肾小球增殖细胞的数量。然而，Ki6896并未抑制肾小球中I型胶原蛋白和纤连蛋白的积累。