Synthesis and evaluation of 1,4-diphenylbutadiene derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) production.

Hiroshi Miyazaki, Hiroshi Sai, Hiroshi Ohmizu, Jun Murakami, Akio Ohtani, Tsuyoshi Ogiku

Medicinal Chemistry Laboratory, Mitsubishi Tanabe Pharma Co., Ltd, 3-16-89, Kashima, Yodogawa, Osaka 532-8505, Japan. miyazaki.hiroshi@me.mt-pharma.co.jp

Bioorganic & medicinal chemistry 2010 Mar 1

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Butadiene-imide 1 (T-686) derivatives were synthesized and evaluated for their inhibitory activity against PAI-1 production and their ADMET (DMPK and toxicology) profiles. Among these derivatives, compound 15k (T-2639) showed good antithrombotic activity in two rat thrombosis models without affecting bleeding time, indicating reduction of haemorrhagic risk. We also describe in this report a practical synthesis of 15k suitable for scale-up using Z,E-selective Stobbe condensation. Copyright 2010 Elsevier Ltd. All rights reserved.

Citation

Hiroshi Miyazaki, Hiroshi Sai, Hiroshi Ohmizu, Jun Murakami, Akio Ohtani, Tsuyoshi Ogiku. Synthesis and evaluation of 1,4-diphenylbutadiene derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) production. Bioorganic & medicinal chemistry. 2010 Mar 1;18(5):1968-79