دورية أكاديمية
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.
| العنوان: | 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. |
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| المؤلفون: | Geuns-Meyer S; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Cee VJ; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Deak HL; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Du B; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Hodous BL; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Nguyen HN; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Olivieri PR; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Schenkel LB; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Vaida KR; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Andrews P; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Bak A; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Be X; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Beltran PJ; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Bush TL; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Chaves MK; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Chung G; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Dai Y; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Eden P; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Hanestad K; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Huang L; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Lin MH; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Tang J; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Ziegler B; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Radinsky R; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Kendall R; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Patel VF; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States., Payton M; †Departments of Medicinal Chemistry, ‡Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, ∥Molecular Structure, and ⊥Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2015 Jul 09; Vol. 58 (13), pp. 5189-207. Date of Electronic Publication: 2015 May 31. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Drug Discovery*, Aurora Kinases/*antagonists & inhibitors , Drug Resistance, Multiple/*drug effects , Drug Resistance, Neoplasm/*drug effects , Neoplasms/*drug therapy , Phthalazines/*pharmacology , Protein Kinase Inhibitors/*pharmacology, Animals ; Cell Proliferation/drug effects ; Female ; Humans ; Mice ; Mice, Nude ; Molecular Structure ; Neoplasms/enzymology ; Neoplasms/pathology ; Rats ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays |
| مستخلص: | 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. |
| المشرفين على المادة: | 0 (N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine) 0 (Phthalazines) 0 (Protein Kinase Inhibitors) EC 2.7.11.1 (Aurora Kinases) |
| تواريخ الأحداث: | Date Created: 20150514 Date Completed: 20151002 Latest Revision: 20150709 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1021/acs.jmedchem.5b00183 |
| PMID: | 25970324 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.5b00183 |