Synthesis and evaluation of 1,4-diphenylbutadiene derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) production |
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| Authors: | Hiroshi Miyazaki Hiroshi Sai Hiroshi Ohmizu Jun Murakami Akio Ohtani Tsuyoshi Ogiku |
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| Affiliation: | 1. Medicinal Chemistry Laboratory, Mitsubishi Tanabe Pharma Co., Ltd, 3-16-89, Kashima, Yodogawa, Osaka 532-8505, Japan;2. Pharmacology Laboratory, Mitsubishi Tanabe Pharma Co., Ltd, 2-2-50, Kawagishi, Toda, Saitama 335-8505, Japan |
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| Abstract: | 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. |
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