R-268712, an orally active transforming growth factor-β type I receptor inhibitor, prevents glomerular sclerosis in a Thy1 nephritis model

Hideki Terashima; Mikio Kato; Masayuki Ebisawa; Hideki Kobayashi; Kanae Suzuki; Yoshikazu Nezu; Toshio Sada

doi:10.1016/j.ejphar.2014.03.045

R-268712, an orally active transforming growth factor-β type I receptor inhibitor, prevents glomerular sclerosis in a Thy1 nephritis model

Eur J Pharmacol. 2014 Jul 5:734:60-6. doi: 10.1016/j.ejphar.2014.03.045. Epub 2014 Apr 12.

Authors

Hideki Terashima¹, Mikio Kato², Masayuki Ebisawa³, Hideki Kobayashi², Kanae Suzuki⁴, Yoshikazu Nezu⁵, Toshio Sada⁶

Affiliations

¹ 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.
² Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
³ Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
⁴ Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
⁵ Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.
⁶ Biological Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

PMID: 24726873
DOI: 10.1016/j.ejphar.2014.03.045

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.

Keywords: ALK-5 inhibitor; Fibrosis; Glomerulonephritis; TGF-β; UUO.

MeSH terms

Administration, Oral
Animals
Dose-Response Relationship, Drug
Fibrosis / prevention & control
Glomerulonephritis / pathology*
Kidney / drug effects
Kidney / pathology
Male
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Pyrazoles / administration & dosage
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Pyridines / administration & dosage
Pyridines / chemistry
Pyridines / pharmacology*
Rats
Receptor, Transforming Growth Factor-beta Type I
Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
Sclerosis / prevention & control
Ureteral Obstruction / pathology

Substances

2-(4-(2-fluoro-5-(3-(6-methylpyridine-2-yl)-1H-pyrazol-4-yl)phenyl)pyrazol-1-yl)ethanol
Protein Kinase Inhibitors
Pyrazoles
Pyridines
Receptors, Transforming Growth Factor beta
Protein Serine-Threonine Kinases
Receptor, Transforming Growth Factor-beta Type I
Tgfbr1 protein, rat