Search

Your search keyword '"Tisha San Miguel"' showing total 2 results
Start Over Author "Tisha San Miguel" Journal bioorganicmedicinal chemistry letters
2 results on '"Tisha San Miguel"'

1. The optimization of aminooxadiazoles as orally active inhibitors of Cdc7

Author

Alexander J. Pickrell, Tisha San Miguel, Kelvin K. C. Sham, Christopher H. Fotsch, Andreas Reichelt, Leeanne Zalameda, Matthew P. Bourbeau, Aaron C. Siegmund, John G. Allen, Heller Scott Francis, Sonia Escobar, Julie M. Bailis, Paul E. Harrington, Tammy L. Bush, Jessica Orf, Helming Tan, Faye Hsieh, Michael J. Frohn, Minqing Rong, and Dean Hickman

Subjects
Clinical Biochemistry, Pharmaceutical Science, Mice, Nude, Cell Cycle Proteins, Pharmacology, Protein Serine-Threonine Kinases, Biochemistry, chemistry.chemical_compound, Mice, Structure-Activity Relationship, Pharmacokinetics, Drug Discovery, Animals, Isoquinoline, Molecular Biology, IC50, Cell potency, Protein Kinase Inhibitors, Oxadiazoles, Molecular Structure, Kinase, Organic Chemistry, Glutathione, Xenograft Model Antitumor Assays, Rats, Disease Models, Animal, chemistry, Pharmacodynamics, Molecular Medicine, Female, Selectivity
Abstract

A series of aminooxadiazoles was optimized for inhibition of Cdc7. Early lead isoquinoline 1 suffered from modest cell potency (cellular IC50=0.71 μM measuring pMCM2), low selectivity against structurally related kinases, and high IV clearance in rats (CL=18 L/h/kg). Extensive optimization resulted in azaindole 26 (Cdc7 IC50=1.1 nM, pMCM2 IC50=32 nM) that demonstrated robust lowering of pMCM2 in a mouse pharmacodynamic (PD) model when dosed orally. Modifications to improve the pharmacokinetic profile of this series were guided by trapping experiments with glutathione in rat hepatocytes.

Published
2013

2. N-substituted azaindoles as potent inhibitors of Cdc7 kinase

Author

John G. Allen, Andreas Reichelt, Guomin Yao, Julie M. Bailis, Elizabeth M. Doherty, James R. Falsey, Tisha San Miguel, Leeanne Zalameda, Marian C. Bryan, Michael D. Bartberger, and Mike Frohn

Subjects
Indoles, Stereochemistry, Clinical Biochemistry, Cancer therapy, Pharmaceutical Science, Cell Cycle Proteins, Protein Serine-Threonine Kinases, Biochemistry, Structure-Activity Relationship, Drug Discovery, Structure–activity relationship, Molecule, Animals, Humans, Molecular Biology, Protein Kinase Inhibitors, Indole test, Aza Compounds, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Kinase, Organic Chemistry, DNA replication, Metabolic stability, Rats, Binding conformation, Molecular Medicine
Abstract

Cdc7 kinase is responsible for the initiation and regulation of DNA replication and has been proposed as a target for cancer therapy. We have identified a class of Cdc7 inhibitors based on a substituted indole core. Synthesis of focused indole and azaindole analogs yielded potent and selective 5-azaindole Cdc7 inhibitors with improved intrinsic metabolic stability (ie 36). In parallel, quantum mechanical conformational analysis helped to rationalize SAR observations, led to a proposal of the preferred binding conformation in the absence of co-crystallography data, and allowed the design of 7-azaindole 37 as a second lead in this series.

Published
2012

Catalog

Books, media, physical & digital resources
See catalog results