title: Isosteric analogs of lenalidomide and pomalidomide: synthesis and biological activity.
abstract: A series of analogs of the immunomodulary drugs lenalidomide (1) and pomalidomide (2), in which the amino group is replaced with various isosteres, was prepared and assayed for immunomodulatory activity and activity against cancer cell lines. The 4-methyl and 4-chloro analogs 4 and 15, respectively, displayed potent inhibition of tumor necrosis factor-α (TNF-α) in LPS-stimulated hPBMC, potent stimulation of IL-2 in a human T cell co-stimulation assay, and anti-proliferative activity against the Namalwa lymphoma cell line. Both of these analogs displayed oral bioavailability in rat.
authors.affiliation: Drug Discovery Department, Celgene Corporation, 86 Morris Avenue, Summit, NJ 07901, United States. aruchelman@celgene.com
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Ruchelman
authors.forename: Hon-Wah
authors.initials: HW
authors.lastname: Man
authors.forename: Weihong
authors.initials: W
authors.lastname: Zhang
authors.forename: Roger
authors.initials: R
authors.lastname: Chen
authors.forename: Lori
authors.initials: L
authors.lastname: Capone
authors.forename: Jian
authors.initials: J
authors.lastname: Kang
authors.forename: Anastasia
authors.initials: A
authors.lastname: Parton
authors.forename: Laura
authors.initials: L
authors.lastname: Corral
authors.forename: Peter H
authors.initials: PH
authors.lastname: Schafer
authors.forename: Darius
authors.initials: D
authors.lastname: Babusis
authors.forename: Mehran F
authors.initials: MF
authors.lastname: Moghaddam
authors.forename: Yang
authors.initials: Y
authors.lastname: Tang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Shirley
authors.forename: George W
authors.initials: GW
authors.lastname: Muller
mesh_terms: D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D000077269:Lenalidomide; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; C467566:pomalidomide; D000077269:Lenalidomide