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)

Osborne, James D., Matthews, Thomas P., McHardy, Tatiana, Proisy, Nicolas, Cheung, Kwai-Ming J., Lainchbury, Michael, Brown, Nathan, Walton, Michael I., Eve, Paul D., Boxall, Katherine J., and others. (2016) 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). Journal of Medicinal Chemistry, 59 (11). pp. 5221-5237. ISSN 0022-2623. (doi:10.1021/acs.jmedchem.5b01938) (KAR id:58552)

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Official URL: http://doi.org/10.1021/acs.jmedchem.5b01938

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.

Item Type:	Article
DOI/Identification number:	10.1021/acs.jmedchem.5b01938
Subjects:	Q Science
Institutional Unit:	Schools > School of Natural Sciences > Biosciences
Former Institutional Unit:	Divisions > Division of Natural Sciences > Biosciences
Depositing User:	Michelle Garrett
Date Deposited:	11 Nov 2016 09:39 UTC
Last Modified:	22 Jul 2025 08:57 UTC
Resource URI:	https://kar.kent.ac.uk/id/eprint/58552 (The current URI for this page, for reference purposes)

University of Kent Author Information

Garrett, Michelle D..

Creator's ORCID:	https://orcid.org/0000-0002-3939-1673
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