Article
Acyl guanidine inhibitors of β-secretase (BACE-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis.
Journal of medicinal chemistry - 8 Nov 2012
Gerritz Samuel W, Zhai Weixu, Shi Shuhao, Zhu Shirong, Toyn Jeremy H, Meredith Jere E, Iben Lawrence G, Burton Catherine R, Albright Charles F, Good Andrew C, Tebben Andrew J, Muckelbauer Jodi K, Camac Daniel M, Metzler William, Cook Lynda S, Padmanabha Ramesh, Lentz Kimberley A, Sofia Michael J, Poss Michael A, Macor John E, Thompson Lorin A
Abstract excerpt
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...
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