title: Design and synthesis of small molecule RhoA inhibitors: a new promising therapy for cardiovascular diseases?
abstract: RhoA is a member of Rho GTPases, a subgroup of the Ras superfamily of small GTP-binding proteins. RhoA, as an important regulator of diverse cellular signaling pathways, plays significant roles in cytoskeletal organization, transcription, and cell-cycle progression. The RhoA/ROCK inhibitors have emerged as a new promising treatment for cardiovascular diseases. However, to date, RhoA inhibitors are macromolecules, and to our knowledge, small molecular-based inhibitors have not been reported. In this study, a series of first-in-class small molecular RhoA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. Virtual screening of ∼200,000 compounds, followed by SPR-based binding affinity assays resulted in three compounds with binding affinities to RhoA at the micromolar level (compounds 1-3). Compound 1 was selected for further structure modifications in considering binding activity and synthesis ease. Fourty-one new compounds (1, 12a-v, 13a-h, and 14a-j) were designed and synthesized accordingly. It was found that eight (12a, 12j, 14a, 14b, 14d, 14e, 14 g, and 14h) showed high RhoA inhibition activities with IC(50) values of 1.24 to 3.00 μM. A pharmacological assay indicated that two compounds (14g and 14 h) demonstrated noticeable vasorelaxation effects against PE-induced contraction in thoracic aorta artery rings and served as good leads for developing more potent cardiovascular agents.
authors: School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors: Jing
authors: J
authors: Deng
authors: Enguang
authors: E
authors: Feng
authors: Sheng
authors: S
authors: Ma
authors: Yan
authors: Y
authors: Zhang
authors: Xiaofeng
authors: X
authors: Liu
authors: Honglin
authors: H
authors: Li
authors: Huang
authors: H
authors: Huang
authors: Jin
authors: J
authors: Zhu
authors: Weiliang
authors: W
authors: Zhu
authors: Xu
authors: X
authors: Shen
authors: Liyan
authors: L
authors: Miao
authors: Hong
authors: H
authors: Liu
authors: Hualiang
authors: H
authors: Jiang
authors: Jian
authors: J
authors: Li