title: Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors.
abstract: We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53.
authors.affiliation: Medicinal Chemistry Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. miyazaki.masaki.p3@daiichisankyo.co.jp
authors.forename: Masaki
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Naito
authors.forename: Yuuichi
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yoshida
authors.forename: Haruko
authors.initials: H
authors.lastname: Kawato
authors.forename: Tooru
authors.initials: T
authors.lastname: Okayama
authors.forename: Hironari
authors.initials: H
authors.lastname: Shimizu
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: Yoshinobu
authors.initials: Y
authors.lastname: Shiose
authors.forename: Masashi
authors.initials: M
authors.lastname: Aonuma
authors.forename: Tsunehiko
authors.initials: T
authors.lastname: Soga
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2