Acyl Guanidine Inhibitors of 尾-Secretase (BACE-1): Optimization of a Micromolar Hit to a Nanomolar Lead via Iterative Solid- and Solution-Phase Library Synthesis

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• 作者：Samuel W. Gerritz ; Weixu Zhai ; Shuhao Shi ; Shirong Zhu ; Jeremy H. Toyn ; Jere E. Meredith ; Jr. ; Lawrence G. Iben ; Catherine R. Burton ; Charles F. Albright ; Andrew C. Good ; Andrew J. Tebben ; Jodi K. Muckelbauer ; Daniel M. Camac ; William Metzler ; Lynda S. Cook ; Ramesh Padmanabha ; Kimberley A. Lentz ; Michael J. Sofia ; Michael A. Poss ; John E. Macor ; Lorin A. Thompson ; III
• 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：9208-9223
• 全文大小：676K
• 年卷期：v.55,no.21(November 8, 2012)
• ISSN：1520-4804

文摘

This report describes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation鈭捪€ interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma A尾 levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain A尾 levels were not obtained.