title: Discovery of novel dihydroimidazothiazole derivatives as p53-MDM2 protein-protein interaction inhibitors: synthesis, biological evaluation and structure-activity relationships.
abstract: Starting with Nutlins as an initial lead, we designed and generated bicyclic scaffolds aiming to place cis-bischlorophenyl moiety at the equivalent location where the hydrophobic interaction with MDM2 could be expected. As a result, we discovered novel MDM2 inhibitors possessing a dihydroimidazothiazole scaffold. Further exploration of the side chains on the dihydroimidazothiazole scaffold aided by molecular modeling resulted in compounds exhibiting almost comparable in vitro potency to Nutlin-3a.
authors.affiliation: Lead Discovery & Optimization Research Laboratories II, R&D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan. miyazaki.masaki.p3@daiichisankyo.co.jp
authors.forename: Masaki
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Haruko
authors.initials: H
authors.lastname: Kawato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Naito
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ikeda
authors.forename: Masaya
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kitagawa
authors.forename: Takahiko
authors.initials: T
authors.lastname: Seki
authors.forename: Setsuko
authors.initials: S
authors.lastname: Fukutake
authors.forename: Masashi
authors.initials: M
authors.lastname: Aonuma
authors.forename: Tsunehiko
authors.initials: T
authors.lastname: Soga
mesh_terms: D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy; D060066:Protein Interaction Maps / Q000187:drug effects*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007093:Imidazoles; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2