Design and synthesis of BACE-1 inhibitors utilizing a tertiary hydroxyl motif as the transition state mimic (original) (raw)
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Bioorganic & Medicinal Chemistry Letters, 2010
The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pK a of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Fb production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.
Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors
Bioorganic & Medicinal Chemistry Letters, 2011
This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described.
Structure-based design and synthesis of macrocyclic peptidomimetic β-secretase (BACE-1) inhibitors
Bioorganic & Medicinal Chemistry Letters, 2009
The hydroxyethylene octapeptide inhibitor OM99-2 served as starting point to create the tripeptide inhibitor 1 and its analogues 2a and b. An X-ray co-crystal structure of 1 with BACE-1 allowed the design and syntheses of a series of macrocyclic analogues 3a-h covalently linking the P1 and P3 side-chains. These inhibitors show improved enzymatic potency over their open-chain analogue. Inhibitor 3h also shows activity in a cellular system. Ó 2009 Elsevier Ltd. All rights reserved.
BACE1 inhibitors: Optimization by replacing the P 1 ′ residue with non-acidic moiety
Bioorganic & Medicinal Chemistry Letters, 2008
Recently, we reported potent BACE1 inhibitors KMI-429, -684, and -574 possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays, especially, KMI-429 was confirmed to significantly inhibit Aβ production in vivo. However, acidic moieties at the P4 and P1′ positions of KMI-compounds were thought to be unfavorable for membrane permeability across the blood–brain barrier. Herein, we replaced acidic moieties at the P4 position with other hydrogen bond acceptor groups, and these inhibitors exhibited improved BACE1 inhibitory activities in cultured cells. In this study, we replaced the acidic moieties at the P1′ position with non-acidic and low molecular sized moieties.
Bioorganic & Medicinal Chemistry, 2011
Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on a-phenylnorstatine, a-benzylnorstatine, iso-serine, and b-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC 50 = 0.19 lM) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids.
Preparation and biological evaluation of conformationally constrained BACE1 inhibitors
Bioorganic & Medicinal Chemistry, 2015
The BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1 research efforts, fragment screening revealed that bicyclic thiazine 3 had low millimolar activity against BACE1. Analysis of the co-crystal structure of 3 suggested that potency could be increased through extension toward the S3 pocket and through conformational constraint of the thiazine core. Pursuit of S3-binding groups produced low micromolar inhibitor 6, which informed the S3-design for constrained analogs 7 and 8, themselves prepared via independent, multi-step synthetic routes. Biological characterization of BACE inhibitors 6-8 is described.
Discovery of novel non-peptide inhibitors of BACE-1 using virtual high-throughput screening
Bioorganic & Medicinal Chemistry Letters, 2009
A novel series of isatin-based inhibitors of b-secretase (BACE-1) have been identified using a virtual highthroughput screening approach. Structure-activity relationship studies revealed structural features important for inhibition. Docking studies suggest these inhibitors may bind within the BACE-1 active site through H-bonding interactions involving the catalytic aspartate residues.