Beneficial effects of a novel inhibitor of platelet-derived growth factor receptor autophosphorylation in the rat with mesangial proliferative glomerulonephritis.
1. 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.
Yagi
M
M
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan. m-yagi@kirin.co.jp
Kato
S
S
Kobayashi
Y
Y
Kobayashi
N
N
Iinuma
N
N
Nakamura
K
K
Kubo
K
K
Ohyama
S I
SI
Murooka
H
H
Shimizu
T
T
Nishitoba
T
T
Osawa
T
T
Nagano
N
N
D016475:3T3 Cells; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015432:Glomerulonephritis, Membranoproliferative / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007518:Isoantibodies / Q000276:immunology; D008297:Male; D051379:Mice; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011921:Rats, Inbred WKY; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D012598:Sclerosis; D013601:T-Lymphocytes / Q000276:immunology; D013936:Thymidine / Q000378:metabolism
D000911:Antibodies, Monoclonal; D005353:Fibronectins; D007518:Isoantibodies; C116120:Ki 6896; D011804:Quinolines; C035678:anti-Thy antibody; D003094:Collagen; D010770:Phosphotransferases; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D013936:Thymidine