Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)

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• 作者：James D. Osborne ; Thomas P. Matthews ; Tatiana McHardy ; Nicolas Proisy ; Kwai-Ming J. Cheung ; Michael Lainchbury ; Nathan Brown ; Michael I. Walton ; Paul D. Eve ; Katherine J. Boxall ; Angela Hayes ; Alan T. Henley ; Melanie R. Valenti ; Alexis K. De Haven Brandon ; Gary Box ; Yann Jamin ; Simon P. Robinson ; Isaac M. Westwood ; Rob L. M. van Montfort ; Philip M. Leonard ; Marieke B. A. C. Lamers ; John C. Reader ; G. Wynne Aherne ; Florence I. Raynaud ; Suzanne A. Eccles ; Michelle D. Garrett ; Ian Collins
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：June 9, 2016
• 年：2016
• 卷：59
• 期：11
• 页码：5221-5237
• 全文大小：724K
• 年卷期：0
• ISSN：1520-4804

文摘

Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic–pharmacodynamic (PK–PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition.