RO 09-1679, A NOVEL THROMBIN INHIBITOR

Among the serine proteases involved in thrombosis and hemostasis, thrombin plays a key role in blood coagulation; for example, it converts fibrinogen into fibrin and activates the cofactor V and VIII by a speciffc cleavage of certain peptide bonds next to arginine in physiological substrates. It also acts as a potent agonist for platelet aggregation. Therefore, thrombin is an effective target for an anticoagulant agent. During our screening program for thrombin inhibitors, we isolated a novel inhibitor, Ro 09–1679 (1), from the culture broth of strain NR6773 collected at Minamishitara, Aichi Prefecture, Japan. The strain was identified as Mortierella alpina Peyronel1,2) on the basis of its morphological properties. In this paper, the fermentation, isolation, structural elucidation and biological properties of 1 are reported. The stock culture of the producing organism, M. alpina NR6773, (stored at — 80°C) was thawed and 200 μl was inoculated into five, 500-ml Erlenmeyer flasks each containing 100 ml of seed medium consisting of glycerol 3%, glucose 2%, Polypepton 0.5%, yeast extract 0.2%, NaCl 0.3% and CaCO3 1 %. All were agitated on a rotary shaker for 3 days at 27°C and 190 rpm. Then, the cultures were combined and transferred to a 50-liter jar fermenter containing. © 1992, JAPAN ANTIBIOTICS RESEARCH ASSOCIATION. All rights reserved.