Yamanouchi Pharmaceuticals

Institutefor Consumer Healthcare, Yamanouchi Pharmaceutical Co., Ltd., Tokyo 174-8612, Japan and Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Toyama 930-0194, Japan... 

F. Hirayama, H. Koshio, T. Ishihara, H. Kaizawa, N. Katayama, Y. Taniuchi, and Y. Matsumoto (Yamanouchi Pharmaceutical... 

Kojima Tadao, Takenaka Toichi US Patent No. 4,220,649 September 2, 1980 Assigned to Yamanouchi Pharmaceutical Co., Ltd. (Tokyo, JP)... 

Due to the dual renal and vascular action of AVP, scientists at Yamanouchi Pharmaceuticals became interested in the identification of dual Vla/V2 vasopressin receptor antagonists, particularly because such agents were anticipated to be of unique utility in the treatment of congestive heart failure (CHF), where aberrant AVP secretion appeared responsible for both the onset of hypervolemic hyponatremia and deleterious increases in vascular resistance.14 The resulting drug discovery program ultimately lead to the identification of conivaptan HCl (1). 

This survey of the Western world should not make us forget that Japan also has a thriving pharmaceutical industry. Three firms in particular—Takeda, Sankyo, and Yamanouchi Pharmaceutical Company—are of international repute. Takeda, the largest, is also the oldest, having been founded by the Takeda family in 1781. It has a joint venture with Abbott in the United States. Out of twenty-five blockbuster drugs currently available in the United States, six were discovered in Japan. But Japan remains weak in biotechnological developments, which are the source of much Western drug innovation. 

Another patent by Fujisawa disclosed [31] the structure of FR-901375 from an extract of Pseudomonas chloroaphis No. 2522. While it is a likely H DAC inhibitor, no data have been reported in this regard and the decision seems to have been made to promote FK228 instead as the clinical candidate. In 2001, additional depsipeptide natural products, the spiruchostatins, were reported [32] by Shin-ya s group at the University of Tokyo and Yamanouchi Pharmaceuticals. These compounds were isolated from an extract of Pseudomonas sp. Q71576, on the basis of the ability to increase expression of luciferase driven by the plasminogen activator inhibitor (PAI-1) promoter. Given the structural similarity to FK228, the spiruchostatins were likely to be HDAC inhibitors and this was confirmed in a later patent [33] and in our biochemical studies (see below) with the natural product prepared by total synthesis. 

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