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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Authors
Osborne, JD
Matthews, TP
McHardy, T
Proisy, N
Cheung, K-MJ
Lainchbury, M
Brown, N
Walton, MI
Eve, PD
Boxall, KJ
Hayes, A
Henley, AT
Valenti, MR
De Haven Brandon, AK
Box, G
Jamin, Y
Robinson, SP
Westwood, IM
van Montfort, RLM
Leonard, PM
Lamers, MBAC
Reader, JC
Aherne, GW
Raynaud, FI
Eccles, SA
Garrett, MD
Collins, I
Matthews, TP
McHardy, T
Proisy, N
Cheung, K-MJ
Lainchbury, M
Brown, N
Walton, MI
Eve, PD
Boxall, KJ
Hayes, A
Henley, AT
Valenti, MR
De Haven Brandon, AK
Box, G
Jamin, Y
Robinson, SP
Westwood, IM
van Montfort, RLM
Leonard, PM
Lamers, MBAC
Reader, JC
Aherne, GW
Raynaud, FI
Eccles, SA
Garrett, MD
Collins, I
Document Type
Journal Article
Date
2016-06-09
Date Accepted
2016-05-10
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.
Citation
Journal of medicinal chemistry, 2016, 59 (11), pp. 5221 - 5237
Source Title
Publisher
AMER CHEMICAL SOC
ISSN
0022-2623
eISSN
1520-4804
Research Team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Medicinal Chemistry 2
Pre-Clinical MRI
Hit Discovery & Structural Design
Medicinal Chemistry 1
Medicinal Chemistry 2
Pre-Clinical MRI
Hit Discovery & Structural Design