2-B-P-008 〇坂口 怜子¹、松田 由宗^1,2、岡田 亮^1,3、木稲 真利慧^1,2、木原 隆典²、山本 毅士⁴、猪阪 善隆⁴、永田 龍⁵、森 誠之¹ Reiko Sakaguchi¹, Yoshimune Matsuda^1,2, Ryo Okada^1,3, Marie Konomi^1,2, Takanori Kihara², Takeshi Yamamoto⁴, Yoshitaka Isaka⁴, Ryu Nagata⁵, Masayuki X Mori^{1 1}産業医科大・医・生体物質化学、²北九州市立大学・国際環境工学、³産業医科大・産業保健学部・人間情報科学、⁴大阪大・医学研究科・腎臓内科学、⁵大阪大・薬学研究科 ¹Bio-materials and Chemistry, School of Medicine, University of Occupational and Environmental Health, ²Faculty of Environmental Engineering, The University of Kitakyushu, ³Human, Information and Life Sciences, School of Health Sciences, University of Occupational and Environmental Health, ⁴Department of Nephrology, Graduate School of Medicine, Osaka University, ⁵Graduate School of Pharmaceutical Sciences, Osaka University Nephrotic syndrome is a kidney disorder characterized by high urinary protein and low serum albumin caused by the impairment of glomerular podocytes. It has been reported that Transient Receptor Potential Canonical 6 (TRPC6) mutations found in patients with focal segmental glomerulosclerosis (FSGS) often cause hyperactivated channel currents. Regarding this mechanism, we have previously shown that the disruption of Calmodulin-mediated Ca²⁺-dependent inactivation in TRPC6 channel led to prolonged cation influx and disorganized cytoskeleton in the podocytes. Aside from this, it is also known that in a model animal of chronical damaged kidney, the expression of both TRPC3 and TRPC6 are enhanced, suggesting that both of these molecules could be rational therapeutic targets.
Here, we developed "L862", a novel selective TRPC3/6 dual inhibitor. This compound has a superior pharmacokinetic property compared to previously reported compounds, which allows it to be administered orally. We investigated the effect of L862 in normal rats and puromycin aminonucleoside (PAN)-induced rat nephrotic model. This compound exerted significant improvement of proteinuria, while no apparent toxicities were observed in normal rats. These results suggest that L862 would be a promising therapeutic compound for nephrotic syndrome, as well as other TRPC3/6-related diseases.