Sulfonamides as Selective Na V 1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity.

Autor: Graceffa RF, Boezio AA, Able J; Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States., Altmann S, Berry LM, Boezio C, Butler JR, Chu-Moyer M, Cooke M, DiMauro EF, Dineen TA, Feric Bojic E, Foti RS, Fremeau RT Jr, Guzman-Perez A, Gao H, Gunaydin H, Huang H, Huang L, Ilch C, Jarosh M, Kornecook T; Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States., Kreiman CR, La DS, Ligutti J; Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States., Milgram BC, Lin MJ, Marx IE, Nguyen HN, Peterson EA, Rescourio G, Roberts J, Schenkel L, Shimanovich R, Sparling BA, Stellwagen J, Taborn K, Vaida KR, Wang J, Yeoman J, Yu V, Zhu D, Moyer BD; Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States., Weiss MM

Publikováno v: Journal of medicinal chemistry [J Med Chem] 2017 Jul 27; Vol. 60 (14), pp. 5990-6017. Date of Electronic Publication: 2017 Apr 20.

Purinylpyridinylamino-based DFG-in/αC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling.

Autor: Liu L; Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. Electronic address: lliu@amgen.com., Lee MR; Department of Molecular Structure and Characterization, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA., Kim JL; Department of Molecular Structure and Characterization, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA., Whittington DA; Department of Molecular Structure and Characterization, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA., Bregman H; Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA., Hua Z; Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA., Lewis RT; Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA., Martin MW; Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA., Nishimura N; Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA., Potashman M; Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA., Yang K; Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA., Yi S; Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA., Vaida KR; Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA., Epstein LF; Department of Molecular Structure and Characterization, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA., Babij C; Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA., Fernando M; Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA., Carnahan J; Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA., Norman MH; Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.

Publikováno v: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2016 May 15; Vol. 24 (10), pp. 2215-34. Date of Electronic Publication: 2016 Apr 13.

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.

Autor: 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.

Publikováno v: Journal of medicinal chemistry [J Med Chem] 2015 Jul 09; Vol. 58 (13), pp. 5189-207. Date of Electronic Publication: 2015 May 31.

Discovery of potent and selective 8-fluorotriazolopyridine c-Met inhibitors.

Autor: Peterson EA; Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States., Teffera Y, Albrecht BK, Bauer D, Bellon SF, Boezio A, Boezio C, Broome MA, Choquette D, Copeland KW, Dussault I, Lewis R, Lin MH, Lohman J, Liu J, Potashman M, Rex K, Shimanovich R, Whittington DA, Vaida KR, Harmange JC

Publikováno v: Journal of medicinal chemistry [J Med Chem] 2015 Mar 12; Vol. 58 (5), pp. 2417-30. Date of Electronic Publication: 2015 Mar 03.