Design and Validation of Bicyclic Iminopyrimidinones As Beta Amyloid Cleaving Enzyme-1 (BACE1) Inhibitors: Conformational Constraint to Favor a Bioactive Conformation

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• 作者：Mihirbaran Mandal ; Zhaoning Zhu ; Jared N. Cumming ; Xiaoxiang Liu ; Corey Strickland ; Robert D. Mazzola ; John P. Caldwell ; Prescott Leach ; Michael Grzelak ; Lynn Hyde ; Qi Zhang ; Giuseppe Terracina ; Lili Zhang ; Xia Chen ; Reshma Kuvelkar ; Matthew E. Kennedy ; Leonard Favreau ; Kathleen Cox ; Peter Orth ; Alexei Buevich ; Johannes Voigt ; Hongwu Wang ; Irina Kazakevich ; Brian A. McKittrick ; William Greenlee ; Eric M. Parker ; Andrew W. Stamford
• 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：9331-9345
• 全文大小：635K
• 年卷期：v.55,no.21(November 8, 2012)
• ISSN：1520-4804

文摘

On the basis of our observation that the biaryl substituent of iminopyrimidinone 7 must be in a pseudoaxial conformation to occupy the contiguous S1鈥揝3 subsites of BACE1, we have designed a novel fused bicyclic iminopyrimidinone scaffold intended to favor this bioactive conformation. Strategic incorporation of a nitrogen atom in the new constrained ring allowed us to develop SAR around the S2鈥?binding pocket and ultimately resulted in analogues with low nanomolar potency for BACE1. In particular, optimization of the prime side substituent led to major improvements in potency by displacement of two conserved water molecules from a region near S2鈥? Further optimization of the pharmacokinetic properties of this fused pyrrolidine series, in conjunction with facile access to a rat pharmacodynamic model, led to identification of compound 43, which is an orally active, brain penetrant inhibitor that reduces A尾₄₀ in the plasma, CSF, and cortex of rats in a dose-dependent manner.