Referenced in: none

Automatically associated channels: Kv11.1

Title: 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).

Authors: 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

Journal, date & volume: J. Med. Chem., 2016 Jun 9 , 59, 5221-37

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/27167172

Abstract
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.