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Your search keyword '"Valenti MR"' showing total 2 results
Start Over Author "Valenti MR" Journal journal of medicinal chemistry
2 results on '"Valenti MR"'

1. 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).

Author

Osborne JD, Matthews TP, McHardy T, Proisy N, Cheung KM, 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 RL, Leonard PM, Lamers MB, Reader JC, Aherne GW, Raynaud FI, Eccles SA, Garrett MD, and Collins I

Subjects
4-Aminopyridine chemical synthesis, 4-Aminopyridine chemistry, 4-Aminopyridine pharmacology, Checkpoint Kinase 1 metabolism, Dose-Response Relationship, Drug, Humans, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Pyrazines chemical synthesis, Pyrazines chemistry, Structure-Activity Relationship, 4-Aminopyridine analogs & derivatives, Checkpoint Kinase 1 antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Pyrazines pharmacology
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.

Published
2016
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2. Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors.

Author

Lainchbury M, Matthews TP, McHardy T, Boxall KJ, Walton MI, Eve PD, Hayes A, Valenti MR, de Haven Brandon AK, Box G, Aherne GW, Reader JC, Raynaud FI, Eccles SA, Garrett MD, and Collins I

Subjects
Administration, Oral, Aminopyridines chemical synthesis, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents chemical synthesis, Checkpoint Kinase 1, Child, Colonic Neoplasms enzymology, DNA Damage drug effects, Drug Design, Humans, Mice, Mice, Nude, Mice, Transgenic, N-Myc Proto-Oncogene Protein, Neuroblastoma enzymology, Nuclear Proteins genetics, Oncogene Proteins genetics, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemical synthesis, Protein Kinases metabolism, Pyrimidines chemical synthesis, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Aminopyridines pharmacology, Antineoplastic Agents pharmacology, Colonic Neoplasms drug therapy, Neuroblastoma drug therapy, Protein Kinase Inhibitors pharmacology, Protein Kinases chemistry, Pyrimidines pharmacology
Abstract

Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential antitumor agents, but the most advanced inhibitor series reported to date are not orally bioavailable. A novel series of potent and orally bioavailable 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitrile CHK1 inhibitors was generated by hybridization of two lead scaffolds derived from fragment-based drug design and optimized for CHK1 potency and high selectivity using a cell-based assay cascade. Efficient in vivo pharmacokinetic assessment was used to identify compounds with prolonged exposure following oral dosing. The optimized compound (CCT244747) was a potent and highly selective CHK1 inhibitor, which modulated the DNA damage response pathway in human tumor xenografts and showed antitumor activity in combination with genotoxic chemotherapies and as a single agent.

Published
2012
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