Design of potent and highly selective inhibitors for human β-secretase 2 (memapsin 1), a target for type 2 diabetes

Abstract

Structure-based design and syntheses of potent and highly selective BACE2 inhibitors are described.

Highly Selective and Potent Human β‐Secretase 2 (BACE2) Inhibitors against Type 2 Diabetes: Design, Synthesis, X‐ray Structure and Structure–Activity Relationship Studies

“…Inhibitor 1 is quite potent against BACE1, but it also displayed inhibition toward BACE2 with a K i value of 137 n m which is 76‐fold less potent than BACE1 . K i values for this compound and all other compounds described herein were determined from kinetic data determined under tight‐binding inhibition conditions and using the Morrison equation as described previously …”

“…Therefore, replacement of the methoxybenzyl group with polar functionalities could improve selectivity toward BACE2. We therefore sought to simultaneously insert alcohol and amide polar functionalities by replacing the methoxybenzyl group with an allothreonine isobutylamide and other derivatives . Thus, replacement of the P1′‐methoxybenzylamine of inhibitor 1 with an allothreonine derivative resulted in inhibitor 2 a .…”

“…Opening of epoxide 9 carried on with amine derivatives 16 a – c in isopropanol at 80 °C afforded amino alcohol derivatives 17 a – c . Removal of the Boc group by exposure to TFA followed by coupling of the resulting amines with the suitable carboxylic acids 4 a – d using EDCI and HOBt in the presence of DIPEA led to final compounds 3 a – h (Table ).…”

“…Based on this speculation, we first assessed compound 2 b as the amide N ‐methylated counterpart of compound 2 a . The resulting inhibitor 2 b showed decreased BACE2 potency, but improved selectivity over BACE1 ( K i =80 n m for BACE2 and K i =1812 n m for BACE1) . We then designed compound 2 c in which the sulfonamide moiety of 2 a was replaced by a methyl group.…”

“…For the development of BACE2 inhibitor drugs for diabetes, inhibitor selectivity is critically important and there are only a few limited reports of BACE2 inhibitors with marginal selectivity . We recently reported our preliminary work on the design and synthesis of selective BACE2 inhibitors based on transition‐state isosteres . We have now expanded structure–activity relationship studies, determined a high‐resolution X‐ray structure of a potent and selective inhibitor complexed with BACE1, and created a structural model of inhibitor and BACE2 active site interactions.…”