Imidazo[4,5-b]pyridine Derivatives As Inhibitors of Aurora Kinases: Lead Optimization Studies toward the Identification of an Orally Bioavailable Preclinical Development Candidate

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• 作者：Vassilios Bavetsias ; Jonathan M. Large ; Chongbo Sun ; Nathalie Bouloc ; Magda Kosmopoulou ; Mizio Matteucci ; Nicola E. Wilsher ; Vanessa Martins ; Jhannes Reynisson ; Butrus Atrash ; Amir Faisal ; Frederique
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：July 22, 2010
• 年：2010
• 卷：53
• 期：14
• 页码：5213-5228
• 全文大小：1334K
• 年卷期：v.53,no.14(July 22, 2010)
• ISSN：1520-4804

文摘

Lead optimization studies using 7 as the starting point led to a new class of imidazo[4,5-b]pyridine-based inhibitors of Aurora kinases that possessed the 1-benzylpiperazinyl motif at the 7-position, and displayed favorable in vitro properties. Cocrystallization of Aurora-A with 40c (CCT137444) provided a clear understanding into the interactions of this novel class of inhibitors with the Aurora kinases. Subsequent physicochemical property refinement by the incorporation of solubilizing groups led to the identification of 3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-yl)methyl)-5-methylisoxazole (51, CCT137690) which is a potent inhibitor of Aurora kinases (Aurora-A IC₅₀ = 0.015 ± 0.003 μM, Aurora-B IC₅₀ = 0.025 μM, Aurora-C IC₅₀ = 0.019 μM). Compound 51 is highly orally bioavailable, and in in vivo efficacy studies it inhibited the growth of SW620 colon carcinoma xenografts following oral administration with no observed toxicities as defined by body weight loss.