3,3-Difluoro-3,4,5,6-tetrahydropyridin-2-amines: Potent and permeable BACE-1 inhibitors (original) (raw)
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Based on lead compound 1 identified from the patent literature, we developed novel patentable BACE-1 inhibitors by introducing a cyclic amine scaffold. Extensive SAR studies on both pyrrolidines and piperidines ultimately led to inhibitor 2f, one of the most potent inhibitors synthesized to date.
Discovery of BACE-1 inhibitors using an integrated computational and experimental approach
2014
Abbreviations and nomenclature x Chapter 1. Introduction 1.1 Drug discovery process: from leads to drug candidates Chapter 2. Structure-based design of putative bioactive molecules for BACE-1 37 2.1 Overview of the computational approach 37 2.1.1 Pipeline Pilot 38 2.1.2 eHiTS 40 2.1.3 Ligand selection 41 2.2 Testing the applicability of eHiTS to BACE-1 43 2.3 Design of a virtual library of likely synthetically accessible lead-like compounds 47 2.3.1 Identification of promising ligands 49 2.3.2 Optimisation of library A and identification of two families of putative BACE-1 inhibitors 50 2.4 Analysis of the predicted binding poses of the putative inhibitors 54 2.4.1 Validation of the predicted binding poses with additional docking software 57 2.4.2 Design of a focused library of putative inhibitors 62 2.5 Summary 63 Chapter 3. Synthesis of a library of imidazolidinones 65 3.1 Identification of two possible synthetic routes 65 3.2 Synthetic route to the target imidazolidinones based upon a Pd-catalysed aminoarylation 66 3.2.1 Synthesis of substrates for the Pd-catalysed aminoarylation 67 3.2.2 Investigation of the Pd-catalysed aminoarylation 72 3.2.2.1 Determination of the stereochemistal outcome of the Pd-catalysed aminoarylation 74 3.2.2.2 Rationalisation of the stereochemical outcome of the Pd-catalysed aminoarylation 75 3.2.2.3 Proposed mechanism for the formation of the N-arylated imidazolidinone 27 76 viii 3.2.3 Practicability of the route based upon the Pd-catalysed aminoarylation 3.3 Synthetic route to the target imidazolidinones based upon an iodine-mediated cyclisation reaction 3.3.1 Exploration of synthetic route from benzylallylic amine 3.3.2 Synthesis of the target imidazolidinones 3.3.2.1 Synthesis of substrates for the iodine-mediated cyclisation 3.3.2.2 Synthesis of a focused library of imidazolidinones 3.3.2.3 Determination of the relative configuration of products 3.3.2.4 Rationalisation of the stereochemical outcome of the urea ring formation 3.4 Summary Chapter 4. Biological activity evaluation of BACE-1 imidazolidinone putative inhibitors 4.1 Assay for biological activity evaluation against BACE-1 4.2 Biological activity measurements 4.2.1 Analysis of structure-activity relationship 4.3 Design of structural analogues of active compounds 4.3.1 Synthesis of monosubstituted analogues 4.3.2 Synthesis of bisubstituted analogues 4.3.3 Biological evaluation of a second generation of analogues 4.4 Assessing inhibitor selectivity for BACE-1 4.4.1 Biological activity measurements 4.5 Summary 4.6 Conclusion and future directions Chapter 5. Experimental
Bioorganic & Medicinal Chemistry, 2010
In a preceding study we have described the development of a new hydroxyethylene (HE) core motif displaying P1 aryloxymethyl and P1 0 methoxy substituents delivering potent BACE-1 inhibitors. In a continuation of this work we have now explored the SAR of the S1 0 pocket by introducing a set of P1 0 alkoxy groups and evaluated them as BACE-1 inhibitors. Previously the P1 and P1 0 positions of the classical HE template have been relatively little explored due to the complexity of the chemical routes involved in modifications at these positions. However, the chemistries developed for the current HE template renders substituents in both the P1 and P1 0 positions readily available for SAR exploration. The BACE-1 inhibitors prepared displayed K i values in the range of 1-20 nM, where the most potent compounds featured small P1 0 groups. The cathepsin D selectivity which was high for the smallest P1 0 substituents (P1 0 = ethoxy, fold selectively >1500) dropped for larger groups (P1 0 = benzyloxy, fold selectivity of 3). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity.
Bioorganic Chemistry, 2020
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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.
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, 2010
The identification of highly selective small molecule di-substituted pyridinyl aminohydantoins as bsecretase inhibitors is reported. The more potent and selective analogs demonstrate low nanomolar potency for the BACE1 enzyme as measured in a FRET assay, and exhibit comparable activity in a cellbased (ELISA) assay. In addition, these pyridine-aminohydantoins are highly selectivity (>500Â) against the other structurally related aspartyl proteases BACE2, cathepsin D, pepsin and renin. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported aminohydantoin 3a. We have taken advantage of the amino acid difference between the BACE1 and BACE2 at the S2 0 pocket (BACE1 Pro 70 changed to BACE2 Lys 86 ) to build ligands with >500-fold selectivity against BACE2. The addition of large substituents on the targeted ligand at the vicinity of this aberration has generated a steric conflict between the ligand and these two proteins, thus impacting the ligand's affinity and selectivity. These ligands have also shown an exceptional selectivity against cathepsin D (>5000-fold) as well as the other aspartyl proteases mentioned. One of the more potent compounds (S)-39 displayed an IC 50 value for BACE1 of 10 nM, and exhibited cellular activity with an EC 50 value of 130 nM in the ELISA assay.
BACE1 inhibitors: A head group scan on a series of amides
Bioorganic & Medicinal Chemistry Letters, 2013
A series of amides bearing a variety of amidine head groups was investigated as BACE1 inhibitors with respect to inhibitory activity in a BACE1 enzyme as well as a cell-based assay. Determination of their basicity as well as their properties as substrates of P-glycoprotein revealed that a 2-amino-1,3-oxazine head group would be a suitable starting point for further development of brain penetrating compounds for potential Alzheimer's disease treatment.