Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes

Sandgren, VeronicaLinköpings universitet,Organisk Kemi,Tekniska högskolan (author)

Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core : Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes

On the day of the defence day the status of this article was Manuscript.
A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC50 values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyses were performed on selected compounds, and enzyme-inhibitor interactions are discussed.

Alzheimer’s disease; BACE-1 inhibition; Macrocycles; Hydroxyethylamine (HEA) isostere

Agback, TatianaMedivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden (author)
Johansson, Per-OlaMedivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden (author)
Lindberg, JimmyMedivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden (author)
Kvarnström, IngemarLinköpings universitet,Organisk Kemi,Tekniska högskolan(Swepub:liu)ingkv34 (author)
Samuelsson, BertilMedivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden (author)
Belda, OscarMedivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden (author)
Dahlgren, AndersLinköpings universitet,Organisk Kemi,Tekniska högskolan(Swepub:liu)andda41 (author)
Linköpings universitetOrganisk Kemi (creator_code:org_t)

In:Bioorganic & Medicinal Chemistry: Elsevier29:14, s. 4377-43890968-08961464-3391

By the author/editor: Sandgren, Veroni ...; Agback, Tatiana; Johansson, Per-O ...; Lindberg, Jimmy; Kvarnström, Inge ...; Samuelsson, Bert ...; show more...; Belda, Oscar; Dahlgren, Anders; show less...

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