2. Academic Validation
  3. 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)

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)

  • J Med Chem. 2016 Jun 9;59(11):5221-37. doi: 10.1021/acs.jmedchem.5b01938.
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 1,  Marieke B A C Lamers 1,  John C Reader 1,  G Wynne Aherne,  Florence I Raynaud,  Suzanne A Eccles,  Michelle D Garrett,  Ian Collins
Affiliations

Affiliation

  • 1 Sareum Ltd. , Cambridge CB22 3FX, U.K.
PMID: 27167172 DOI: 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.

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