Discovery of N-(4-(3-(2-Aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine (AMG 900), A Highly Selective, Orally Bioavailable Inhibitor of Aurora Kinases with Activity against Multidrug-Resistant Cancer Cell Lines | Zendy

Stephanie Geuns-Meyer | Zendy; Victor J. Cee | Zendy; Holly L. Deak | Zendy; Bingfan Du | Zendy; Brian L. Hodous | Zendy; Hanh Nho Nguyen | Zendy; Philip R. Olivieri | Zendy; Laurie B. Schenkel | Zendy; Karina R. Vaida | Zendy; Paul S. Andrews | Zendy; Annette Bak | Zendy; Xuhai Be | Zendy; Pedro J. Beltran | Zendy; Tammy L. Bush | Zendy; Mary K. Chaves | Zendy; Grace Chung | Zendy; Yang Dai | Zendy; Patrick Eden | Zendy; Kelly Hanestad | Zendy; Liyue Huang | Zendy; Min-Hwa Jasmine Lin | Zendy; Jin Tang | Zendy; Beth Ziegler | Zendy; Robert Radinsky | Zendy; Richard Kendall | Zendy; Vinod F. Patel | Zendy; Marc Payton | Zendy

Open Access

Discovery of N-(4-(3-(2-Aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine (AMG 900), A Highly Selective, Orally Bioavailable Inhibitor of Aurora Kinases with Activity against Multidrug-Resistant Cancer Cell Lines

Author(s) -

Stephanie Geuns-Meyer,

Victor J. Cee,

Holly L. Deak,

Bingfan Du,

Brian L. Hodous,

Hanh Nho Nguyen,

Philip R. Olivieri,

Laurie B. Schenkel,

Karina R. Vaida,

Paul S. Andrews,

Annette Bak,

Xuhai Be,

Pedro J. Beltran,

Tammy L. Bush,

Mary K. Chaves,

Grace Chung,

Yang Dai,

Patrick Eden,

Kelly Hanestad,

Liyue Huang,

Min-Hwa Jasmine Lin,

Jin Tang,

Beth Ziegler,

Robert Radinsky,

Richard Kendall,

Vinod F. Patel,

Marc Payton

Publication year - 2015

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/acs.jmedchem.5b00183

Subject(s) - chemistry , pharmacokinetics , pharmacology , bioavailability , potency , in vivo , pharmacodynamics , in vitro , ic50 , metabolic stability , drug discovery , stereochemistry , biochemistry , microbiology and biotechnology , biology , medicine

Efforts to improve upon the physical properties and metabolic stability of Aurora kinase inhibitor 14a revealed that potency against multidrug-resistant cell lines was compromised by increased polarity. Despite its high in vitro metabolic intrinsic clearance, 23r (AMG 900) showed acceptable pharmacokinetic properties and robust pharmacodynamic activity. Projecting from in vitro data to in vivo target coverage was not practical due to disjunctions between enzyme and cell data, complex and apparently contradictory indicators of binding kinetics, and unmeasurable free fraction in plasma. In contrast, it was straightforward to relate pharmacokinetics to pharmacodynamics and efficacy by following the time above a threshold concentration. On the basis of its oral route of administration, a selectivity profile that favors Aurora-driven pharmacology and its activity against multidrug-resistant cell lines, 23r was identified as a potential best-in-class Aurora kinase inhibitor. In phase 1 dose expansion studies with G-CSF support, 23r has shown promising single agent activity.

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