Core refinement toward permeable β-secretase (BACE-1) inhibitors with low hERG activity

T Ginman, J Viklund, J Malmström, J Blid…

Index: Ginman, Tobias; Viklund, Jenny; Malmstroem, Jonas; Blid, Jan; Emond, Rikard; Forsblom, Rickard; Johansson, Anh; Kers, Annika; Lake, Fredrik; Sehgelmeble, Fernando; Sterky, Karin J.; Bergh, Margareta; Lindgren, Anders; Johansson, Patrik; Jeppsson, Fredrik; Faelting, Johanna; Gravenfors, Ylva; Rahm, Fredrik Journal of Medicinal Chemistry, 2013 , vol. 56, # 11 p. 4181 - 4205

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Citation Number: 25

Abstract

By use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of ...