Discovery of 3-Alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as Selective, Orally Bioavailable CHK1 Inhibitors

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• 作者：Michael Lainchbury ; Thomas P. Matthews ; Tatiana McHardy ; Kathy J. Boxall ; Michael I. Walton ; Paul D. Eve ; Angela Hayes ; Melanie R. Valenti ; Alexis K. de Haven Brandon ; Gary Box ; G. Wynne Aherne ; John C. Reader ; Florence I. Raynaud ; Suzanne A. Eccles ; Michelle D. Garrett ; Ian Collins
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：10229-10240
• 全文大小：448K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential antitumor agents, but the most advanced inhibitor series reported to date are not orally bioavailable. A novel series of potent and orally bioavailable 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitrile CHK1 inhibitors was generated by hybridization of two lead scaffolds derived from fragment-based drug design and optimized for CHK1 potency and high selectivity using a cell-based assay cascade. Efficient in vivo pharmacokinetic assessment was used to identify compounds with prolonged exposure following oral dosing. The optimized compound (CCT244747) was a potent and highly selective CHK1 inhibitor, which modulated the DNA damage response pathway in human tumor xenografts and showed antitumor activity in combination with genotoxic chemotherapies and as a single agent.