Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors.

Autor: Cee VJ; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Chavez F Jr; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Herberich B; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Lanman BA; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Pettus LH; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Reed AB; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Wu B; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Wurz RP; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Andrews KL; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Chen J; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Hickman D; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Laszlo J 3rd; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Lee MR; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Guerrero N; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Mattson BK; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Nguyen Y; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Mohr C; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Rex K; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Sastri CE; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Wang P; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Wu Q; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Wu T; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Xu Y; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Zhou Y; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Winston JT; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Lipford JR; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Tasker AS; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States., Wang HL; Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2016 Feb 12; Vol. 7 (4), pp. 408-12. Date of Electronic Publication: 2016 Feb 12 (Print Publication: 2016).
DOI: 10.1021/acsmedchemlett.5b00403
Abstrakt: The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization and developed a series of 13-membered macrocycles. The structure-activity relationships of the macrocyclic linker were systematically explored, leading to the identification of 9c as a potent, subnanomolar inhibitor of Pim-1 and -2. This molecule also potently inhibited Pim kinase activity in KMS-12-BM, a multiple myeloma cell line with relatively high endogenous levels of Pim-1/2, both in vitro (pBAD IC50 = 25 nM) and in vivo (pBAD EC50 = 30 nM, unbound), and a 100 mg/kg daily dose was found to completely arrest the growth of KMS-12-BM xenografts in mice.
Databáze: MEDLINE
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