Discovery of novel dihydroimidazothiazole derivatives as p53-MDM2 protein-protein interaction inhibitors: synthesis, biological evaluation and structure-activity relationships

  • Bioorg Med Chem Lett. 2012 Oct 15;22(20):6338-42. doi: 10.1016/j.bmcl.2012.08.086.
Masaki Miyazaki  1 ,  Haruko Kawato ,  Hiroyuki Naito ,  Masahiro Ikeda ,  Masaya Miyazaki ,  Mayumi Kitagawa ,  Takahiko Seki ,  Setsuko Fukutake ,  Masashi Aonuma ,  Tsunehiko Soga
Affiliations
  • 1. Lead Discovery & Optimization Research Laboratories II, R&D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan. [email protected]
PMID: 22995624 DOI: 10.1016/j.bmcl.2012.08.086
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.

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