title: R-268712, an orally active transforming growth factor-β type I receptor inhibitor, prevents glomerular sclerosis in a Thy1 nephritis model.
abstract: R-268712 is a novel and specific inhibitor of activin receptor-like kinase 5 (ALK5), a transforming growth factor β (TGF-β) type I receptor. Evaluation of in vitro inhibition indicated that R-268712 is a potent and selective inhibitor of ALK5 with an IC50 of 2.5nM, an approximately 5000-fold more selectivity for ALK5 than p38 mitogen-activated protein kinase (MAPK). Oral administration of R-268712 at doses of 1, 3 and 10mg/kg also inhibited the development of renal fibrosis in a dose-dependent manner in a unilateral ureteral obstruction (UUO) model. Additionally, we evaluated the efficacy of R-268712 in a heminephrectomized anti-Thy1 glomerulonephritis model at doses of 0.3 and 1mg/kg. R-268712 reduced proteinuria and glomerulosclerosis significantly with improvement of renal function. Collectively, these results suggested that R-268712 and other ALK5 inhibitors could suppress glomerulonephritis as well as glomerulosclerosis by an inhibitory mechanism that involves suppression of TGF-β signaling.
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: terashima.hideki.jw@daiichisankyo.co.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Terashima
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Kato
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ebisawa
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nezu
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Sada
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis / Q000517:prevention & control; D005921:Glomerulonephritis / Q000473:pathology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D012598:Sclerosis / Q000517:prevention & control; D014517:Ureteral Obstruction / Q000473:pathology
chemical_list: C000594743:2-(4-(2-fluoro-5-(3-(6-methylpyridine-2-yl)-1H-pyrazol-4-yl)phenyl)pyrazol-1-yl)ethanol; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat
keywords: ALK-5 inhibitor; Fibrosis; Glomerulonephritis; TGF-β; UUO