Synthesis and evaluation of 1,4-diphenylbutadiene derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) production.
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.
Miyazaki
Hiroshi
H
Medicinal Chemistry Laboratory, Mitsubishi Tanabe Pharma Co., Ltd, 3-16-89, Kashima, Yodogawa, Osaka 532-8505, Japan. miyazaki.hiroshi@me.mt-pharma.co.jp
Sai
Hiroshi
H
Ohmizu
Hiroshi
H
Murakami
Jun
J
Ohtani
Akio
A
Ogiku
Tsuyoshi
T
D000284:Administration, Oral; D000818:Animals; D002070:Butadienes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004285:Dogs; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D008968:Molecular Conformation; D010654:Phenylbutyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
D002070:Butadienes; D005343:Fibrinolytic Agents; C549980:Methyl 3-(3',5'-dimethoxyphenyl)-2-(1-(4-methylpiperazin-1-ylcarbamoyl)-2-phenylvinyl)-2-butenoate; D010654:Phenylbutyrates; D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors; C012939:1,4-diphenylbutadiene