Identification of Multiple 5-HT4 Partial Agonist Clinical Candidates for the Treatment of Alzheimer鈥檚 Disease

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• 作者：Michael A. Brodney ; David E. Johnson ; Aarti Sawant-Basak ; Karen J. Coffman ; Elena M. Drummond ; Emily L. Hudson ; Katherine E. Fisher ; Hirohide Noguchi ; Nobuaki Waizumi ; Laura L. McDowell ; Alexandros Papanikolaou ; Betty A. Pettersen ; Anne W. Schmidt ; Elaine Tseng ; Kim Stutzman-Engwall ; David M. Rubitski ; Michelle A. Vanase-Frawley ; Sarah Grimwood
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：55
• 期：21
• 页码：9240-9254
• 全文大小：545K
• 年卷期：v.55,no.21(November 8, 2012)
• ISSN：1520-4804

文摘

The cognitive impairments observed in Alzheimer鈥檚 disease (AD) are in part a consequence of reduced acetylcholine (ACh) levels resulting from a loss of cholinergic neurons. Preclinically, serotonin 4 receptor (5-HT₄) agonists are reported to modulate cholinergic function and therefore may provide a new mechanistic approach for treating cognitive deficits associated with AD. Herein we communicate the design and synthesis of potent, selective, and brain penetrant 5-HT₄ agonists. The overall goal of the medicinal chemistry strategy was identification of structurally diverse clinical candidates with varying intrinsic activities. The exposure鈥搑esponse relationships between binding affinity, intrinsic activity, receptor occupancy, drug exposure, and pharmacodynamic activity in relevant preclinical models of AD were utilized as key selection criteria for advancing compounds. On the basis of their excellent balance of pharmacokinetic attributes and safety, two lead 5-HT₄ partial agonist candidates 2d and 3 were chosen for clinical development.