Design and synthesis of dihydrobenzofuran amides as orally bioavailable, centrally active 纬-secretase modulators

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• 作者：Martin Pettersson^a ; ^{martin.pettersson@pfizer.com} ; Douglas S. Johnson^a ; Chakrapani Subramanyam^a ; Kelly R. Bales^c ; Christopher W. am Ende^a ; Benjamin A. Fish^a ; Michael E. Green^a ; Gregory W. Kauffman^a ; Ricardo Lira^a ; Patrick B. Mullins^a ; Thayalan Navaratnam^a ; Subas M. Sakya^a ; Cory M. Stiff^a ; Tuan P. Tran^a ; Beth C. Vetelino^a ; Longfei Xie^a ; Liming Zhang^b ; Leslie R. Pustilnik^b ; Kathleen M. Wood^c ; Christopher J. O&rsquo ; Donnell^a
• 关键词：Alzheimer&rsquo ; s disease ; 纬-Secretase modulators
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 April, 2012
• 卷：22
• 期：8
• 页码：2906-2911
• 文件大小：2667 K

摘要

We report the discovery and optimization of a novel series of dihydrobenzofuran amides as 纬-secretase modulators (GSMs). Strategies for aligning in vitro potency with drug-like physicochemical properties and good microsomal stability while avoiding P-gp mediated efflux are discussed. Lead compounds such as 35 and 43 have moderate to good in vitro potency and excellent selectivity against Notch. Good oral bioavailability was achieved as well as robust brain A尾42 lowering activity at 100 mg/kg po dose.