Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential

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• 作者：Yangbo Feng ; Philip V. LoGrasso ; Olivier Defert ; Rongshi Li
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 24, 2016
• 年：2016
• 卷：59
• 期：6
• 页码：2269-2300
• 全文大小：1701K
• 年卷期：Yangbo Feng
  is Associate Scientific Director of Medicinal Chemistry/Drug Discovery at the Translational Research Institute of the Scripps Research Institute. Dr. Feng has been in charge of the medicinal chemistry efforts for several kinase and non-kinase inhibitor development projects including ROCK. Before joining Scripps in 2004, he was a Senior Scientist and group leader at Discovery Partners Internationals (now part of BioFocus) working on a variety of projects targeting proteases, GPCRs, ion channels, and kinases. Dr. Feng received his Ph.D. in Bioorganic Chemistry from the University of California San Diego, and obtained his postdoctoral training under the guidance of Dr. Kevin Burgess at Texas A&M University. Yangbo is co-inventor of more than 20 patents/patent applications and coauthor of more than 50 peer reviewed manuscripts.
  Philip V. LoGrasso
  is a Professor and Senior Director of Drug Discovery in The Scripps Research Institute. Dr. LoGrasso has been in charge of the discovery biology efforts for several drug discovery projects including ROCK. Before joining Scripps in 2005, he was the Director of Preclinical Research and Development at Avera Pharmaceuticals, a CNS drug development company focused on neurology and psychiatry. Prior to joining Avera, Dr. LoGrasso was a Research Fellow at Merck for 9 years working in the areas of inflammation and molecular neuroscience. Dr. LoGrasso received his Ph.D. in Pharmacology in 1992 at the University of Florida and did postdoctoral training at the Sandoz Research Institute. Phil is co-inventor of 15 patents/patent applications and coauthor of more than 80 peer reviewed manuscripts.
  Olivier Defert
  is cofounder of Amakem and has managed R&D chemistry and regulatory preclinical development since 2010. Olivier led the preclinical development of AMA0076, a ROCK inhibitor in phase 2 for the treatment of glaucoma and ocular hypertension. Prior to Amakem, Olivier was section leader in Medicinal Chemistry at Devgen NV in Belgium for 8 years, with responsibilities in combinatorial chemistry, medicinal chemistry, and preclinical development of the Devgen’s lead ROCK inhibitor for the treatment of Crohn’s disease and PKC inhibitor for the local treatment of psoriasis. He received his Ph.D. in Medicinal Chemistry from the Faculty of Pharmacy in Lille (France) in 2005. He is co-inventor of more than 20 patents/patent applications and coauthor of 4 peer reviewed publications.
  Rongshi Li
  is a Professor of Chemistry and Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Nebraska Medical Center (UNMC). He received his Ph.D. from Dalhousie University in Canada. After postdoctoral studies with George L. Kenyon at University of California, San Francisco, and K. C. Nicolaou at IRORI in San Diego, he spent 14 years in industry and advanced from Scientist to Senior Vice President. Dr. Li began his academic career in 2008 at Moffitt Cancer Center. In 2013, he was recruited to the Center for Drug Discovery, Department of Pharmaceutical Sciences, and Fred and Pamela Buffett Cancer Center, UNMC. Since 2008, Dr. Li has published over 20 peer-reviewed articles, filed and published 28 U.S. and PCT patents, edited two books, and delivered over 30 invited talks.
• ISSN：1520-4804

文摘

Rho kinases (ROCKs) belong to the serine–threonine family, the inhibition of which affects the function of many downstream substrates. As such, ROCK inhibitors have potential therapeutic applicability in a wide variety of pathological conditions including asthma, cancer, erectile dysfunction, glaucoma, insulin resistance, kidney failure, neuronal degeneration, and osteoporosis. To date, two ROCK inhibitors have been approved for clinical use in Japan (fasudil and ripasudil) and one in China (fasudil). In 1995 fasudil was approved for the treatment of cerebral vasospasm, and more recently, ripasudil was approved for the treatment of glaucoma in 2014. In this Perspective, we present a comprehensive review of the physiological and biological functions for ROCK, the properties and development of over 170 ROCK inhibitors as well as their therapeutic potential, the current status, and future considerations.