- Discovery of Indolinone-Based Multikinase Inhibitors as Potential Therapeutics for Idiopathic Pulmonary Fibrosis
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Idiopathic pulmonary fibrosis (IPF) is a serious and deadly disease for which treatment options are limited. The recent approval of antifibrosis agent nintedanib represents one of the first therapeutic approaches for the treatment of IPF. Here, we report novel indolinone-based multikinase inhibitors that target angiogenesis and fibrosis pathways and may serve as potential therapeutics for IPF. KBP-7018 is a novel, tyrosine kinase-selective inhibitor with potent effects on three fibrotic kinases (c-KIT, PDGFR, and RET). The pharmacokinetics (PK) properties of KBP-7018 were favorable in mice, rats, and dogs. In a bleomycin (BLM)-induced mouse pulmonary fibrosis model, 10, 30, and 100 mg/kg daily doses (q.d.) of KBP-7018 improved the 28-day survival rate in a dose-dependent manner. The improved efficacy of KBP-7018 compared to nintedanib provided a certain level of chemical validation for the involvement of PDGFR, c-KIT, and RET in IPF. Thus, KBP-7018 represents a novel multikinase inhibitor with differentiated activity, highly enhanced selectivity, and acceptable PK profiles that will enter phase I clinical trials.
- Huang, Zhenhua,Li, Heran,Zhang, Qian,Lu, Fangzheng,Hong, Mei,Zhang, Zhigang,Guo, Xiaocui,Zhu, Yuanju,Li, Sanming,Liu, Hongzhuo
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p. 1142 - 1147
(2017/11/15)
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- FUROISOQUINOLINE DERIVATIVE AND USE THEREOF
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The present invention provides a compound represented by the formula ???wherein A represents (1) a bond, (2) a group represented by the formula -CRa=CRb- (Ra and Rb each represent a hydrogen atom or C1-6 alkyl) and the like; R1 represents (1) cyano or (2) an optionally esterified or amidated carboxyl group; R2 represents(1) a hydrogen atom, (2) an optionally substituted hydroxy group,(3) an optionally substituted amino group and the like; R3 and R4 each represent a hydrogen atom and the like; R5 represents a hydrogen atom and the like; R6 represents an optionally substituted hydroxy group and the like; R7and R8 each represent an optionally substituted hydrocarbon group and the like; R9 and R10 each represent (1) a hydrogen atom and the like; Y represents an optionally substituted methylene group; and n represents 0 or 1, or a salt thereof, which has an excellent phosphodiesterase IV inhibiting action.
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Page/Page column 41
(2010/02/11)
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