And the Clinical Aspect of Anti RhoKinase Therapy

H. Hidaka1 ()) ■ Y. Suzuki2 ■ M. Shibuya3 ■ Y. Sasaki4

1 Western Therapeutics Institute, 100-32 Yagotohonmachi, Showa-ku, 466-0825 Nagoya, Japan

[email protected]

2 Department of Neurosurgery, Nagoya Daini Red Cross Hospital, 2-9 Myoken, Showa-ku, 466-8650 Nagoya, Japan

3 Chukyo Hospital, 1-1-10 Sanjo, Minami-ku, 457-8510 Nagoya, Japan

4 Department of Pharmacology, Pharmaceutical Science, Kitasato University, 5-9-1 Shirokane, Minato-ku, 108-8641 Tokyo, Japan

1 Discovery of Isoquinolinesulfonamide as a Protein Kinase Inhibitor 412

1.1 History of Discovery 412

1.2 Why Are Isoquinolinesulfonamides Specific for Protein Kinases? 415

2 Rho-Kinase Inhibitor and Its Pharmacological Properties 418

2.1 Relationship Between Rho-Kinase Inhibition and the Modulation of Physiological Function 418

2.2 A Novel Rho-Kinase Inhibitor and Its Perspective 420

3 Clinical Application of Isoquinolinesulfonamide to Human Cerebral Vascular Diseases 422

3.1 Demonstration of the Therapeutic Effect of HA1077 on Cerebral Vasospasm and Infarction Using Model Animals 423

3.1.1 Effect on Subarachnoid Hemorrhage 423

3.1.2 Effect on Cerebral Ischemia 425

3.2 Clinical Application of HA1077 to 100,000 Patients 426

3.2.1 Anti-vasospasmic Effect 426

3.2.2 Intra-arterial Use ofHA1077 428

3.2.3 Effect of HA1077 on Cerebral Infarction 428

References 429

Abstract The light of molecular pharmacology research has been focused on protein kinase inhibitor sulfonamide derivatives since 1978. Our studies on naphthalene and iso-quinoline sulfonamide derivatives over the last 25 years have achieved a pronounced contribution toward elucidating the physiological function of various protein kinases and, moreover, toward developing a new type of medicine. This chapter relates to the discovery of new protein kinase inhibitors, their mechanisms of action, and their clinical application in Japan.

Keywords Calmodulin antagonist • W-7 • Naphthalenesulfonamide • Isoquinolinesulfonamide • H-7 • H-8 • H-9 • HA1077 • Rho kinase inhibitor • Vasodilator • Phosphorylation of MLC20 • Vasospasm • Cerebral ischemia • Subarachnoid hemorrhage • Cerebral infarction

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