Design and synthesis of statine-containing BACE inhibitors

Utilizing structure-based techniques and solid-phase synthesis, statine-based tetrapeptide BACE inhibitors were designed and synthesized using a heptapeptide BACE transition-state mimetic, 1, as the starting point. Structure–activity relationship studies at the P₃, P₂, and P₂′ positions as well as the N-terminal capping group on scaffold 5 led to the discovery of potent inhibitors 27, 32, and 34 (IC₅₀ <100 nM). In addition, computational analysis and the X-ray structure of BACE–inhibitor 38 are discussed.     

Design and synthesis of thiophene dihydroisoquinolines as novel BACE1 inhibitors

Utilizing a structure based design approach, combined with extensive medicinal chemistry execution, highly selective, potent and novel BACE1 inhibitor 8 (BACE1 Alpha assay IC₅₀ = 8 nM) was made from a weak μM potency hit in an extremely efficient way. The detailed SAR and general design approaches will be discussed.     

beta-N-Biaryl ether sulfonamide hydroxamates as potent gelatinase inhibitors: part 1. Design, synthesis, and lead identification

A new series of beta-N-biaryl ether sulfonamide hydroxamates as novel gelatinase inhibitors is described. These compounds exhibit good potency for MMP-2 and MMP-9 without inhibiting MMP-1. The structure-activity relationships (SAR) reveal the biaryl ether type P1' moiety together with methanesulfonamide is the optimal combination that provides inhibitory activity of MMP-9 in the single-digit nanomolar range.     

New substituted aminopyrimidine derivatives as BACE1 inhibitors: in silico design,synthesis and biological assays

We report in this work new substituted aminopyrimidine derivatives acting as inhibitors of the catalytic site of BACE1. These compounds were obtained from a molecular modeling study. The theoretical and experimental study reported here was carried out in several steps: docking analysis, Molecular Dynamics (MD) simulations, Quantum Theory Atom in Molecules (QTAIM) calculations, synthesis and bioassays and has allowed us to propose some compounds of this series as new inhibitors of the catalytic site of BACE1. The QTAIM study has allowed us to obtain an excellent correlation between the electronic densities and the experimental data of IC₅₀. Also, using combined techniques (MD simulations and QTAIM calculations) enabled us to describe in detail the molecular interactions that stabilize the different L-R complexes. In addition, our results allowed us to determine what portion of these compounds should be changed in order to increase their affinity with the BACE1. Another interesting result is that a sort of synergism was observed when the effects of these new catalytic site inhibitors were combined with Ac-Tyr5-Pro6-Tyr7-Asp8-Ile9-Pro10-Leu11-NH₂, which we have recently reported as a modulator of BACE1 acting on its exosite.     

Daedalols A-C, fungal-derived BACE1 inhibitors

Bioassay-guided fractionation of an extract prepared from the fruiting bodies of a Daedalea sp. has led to the isolation of daedalols A-C (1-3). The structures of these new triterpenes were elucidated based on extensive NMR spectroscopic and mass spectrometric measurements. Assignment of the relative configuration of 3 required the preparation of a suitable derivative via a Payne rearrangement. The aspartic protease BACE1, an Alzheimer's drug target, was inhibited by 3 with an IC(50) value of 14.2 μM.     

Design, synthesis, and evaluation of tetrahydroquinoline and pyrrolidine sulfonamide carbamates as gamma-secretase inhibitors

Gamma-secretase is a key enzyme involved in the production of beta-amyloid peptides which are believed to play a critical role in the onset and progression of Alzheimer's disease (AD). As such, inhibition of gamma-secretase has been an attractive approach to AD therapy. In this paper, the design, synthesis, and evaluation of tetrahydroquinoline and pyrrolidine sulfonamide carbamates as gamma-secretase inhibitors are described.     

Design and synthesis of potent beta-secretase (BACE1) inhibitors with P1' carboxylic acid bioisosteres

Recently, we reported potent and small-sized beta-secretase (BACE1) inhibitors KMI-420 and KMI-429 in which we replaced the Glu residue at the P4 position of KMI-260 and KMI-360, respectively, with a 1H-tetrazole-5-carbonyl DAP (L-alpha,beta-diaminopropionic acid) residue. At the P1' position, these compounds contain one or two carboxylic acid groups, which are unfavorable for crossing the blood-brain barrier. Herein, we report BACE1 inhibitors with P1' carboxylic acid bioisosteres in order to develop practical anti-Alzheimer's disease drugs. Among them, tetrazole ring-containing compounds, KMI-570 (IC50=4.8 nM) and KMI-684 (IC50=1.2 nM), exhibited significantly potent BACE1 inhibitory activities.     

Molecular modeling,synthesis, and activity studies of novel biaryl and fused-ring BACE1 inhibitors

A series of transition state analogues of beta-secretases 1 and 2 (BACE1, 2) inhibitors containing fused-ring or biaryl moieties were designed computationally to probe the S2 pocket, synthesized, and tested for BACE1 and BACE2 inhibitory activity. It has been shown that unlike the biaryl analogs, the fused-ring moiety is successfully accommodated in the BACE1 binding site resulting in the ligands with excellent inhibitory activity. Ligand 5b reduced 65% of Aβ40 production in N2a cells stably transfected with Swedish human APP.     

Design,synthesis, and enzymatic characterization of quinazoline-based CYP1A2 inhibitors

Cytochrome P450 isozyme 1A2 (CYP1A2) is one main xenobiotic metabolizing enzyme in humans. It has been associated with the bioactivation of procarcinogens, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco specific and potent pulmonary carcinogen. This work describes the computational design and in-silico screening of potential CYP1A2 inhibitors, their chemical synthesis, and enzymatic characterization with the ultimate aim of assessing their potential as cancer chemopreventive agents. To achieve this, a combined classifiers model was used to screen a library of quinazoline-based molecules against known CYP1A2 inhibitors, non-inhibitors, and substrates to predict which quinazoline candidates had a better probability as an inhibitor. Compounds with high probability of CYP1A2 inhibition were further computationally evaluated via Glide docking. Candidates predicted to have selectivity and high binding affinity for CYP1A2 were synthesized and assayed for their enzymatic inhibition of CYP1A2, leading to the discovery of novel and potent quinazoline-based CYP1A2 inhibitors.     

Structure-guided design and synthesis of P1' position 1-phenylcycloalkylamine-derived pentapeptidic BACE1 inhibitors

Previously, we reported potent pentapeptidic BACE1 inhibitors with the hydroxymethylcarbonyl isostere as a substrate transition-state mimic. To improve the in vitro potency, we further reported pentapeptidic inhibitors with carboxylic acid bioisosteres at the P(4) and P1' positions. In the current study, we screened new P1' position 1-phenylcycloalkylamine analogs to find non-acidic inhibitors that possess double-digit nanomolar range IC(50) values. An extensive structure-activity relationship study was performed with various amine derivatives at the P1' position. The most potent inhibitor of this pentapeptide series, KMI-1830, possessing 1-phenylcyclopentylamine at the P1' position had an IC(50) value of 11.6 nM against BACE1 in vitro enzymatic assay.     

Design, synthesis, and evaluation of Leu*Ala hydroxyethylene-based non-peptide beta-secretase (BACE) inhibitors

With the aim of developing small molecular non-peptide beta-secretase (BACE) inhibitors, Leu*Ala hydroxyethylene (HE) was investigated as a scaffold to design and synthesize a series of compounds. Taking advantage of efficient combinatorial synthesis approaches and molecular modeling, extensive structure-activity relationship (SAR) studies were carried out on the N- and C-terminal residues of the Leu*Ala HE scaffold. Isobutyl amine was found to be an optimal C-cap, and suitable hydroxylalkylamines at the 3-position and nitro or methyl(methylsulfonyl)amine at the 5-position of isophthalamide as the N-terminus could form additional hydrogen bonds with BACE active sites and help improve potency. Many new potent non-peptide BACE inhibitors were identified in this study. Among them, compounds 37 and 44 exhibited excellent enzyme-inhibiting potency, comparable to that of OM99-2, and obvious inhibitory effects in cell-based assay with low molecular weights (<600).     

Novel non-peptidic and small-sized BACE1 inhibitors

Recently, we reported substrate-based beta-secretase (BACE1) inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. These inhibitors showed potent BACE1 inhibitory activities (approximately 1.2 nM IC(50)). In order to improve in vivo enzymatic stability and permeability across the blood-brain barrier, these penta-peptidic inhibitors would need to be further optimized. On the other hand, non-peptidic inhibitors possessing isophthalic residue at the P(2) position were reported from other research groups. We selected isophthalic-type aromatic residues at the P(2) position and an HMC isostere at the P(1) position as lead compounds. On the basis of the design approach focused on the conformer of docked inhibitor in BACE1, we found novel non-peptidic and small-sized BACE1 inhibitors possessing a 2,6-pyridinedicarboxylic, chelidamic or chelidonic residue at the P(2) position.     

Sebestenoids A-D, BACE1 inhibitors from Cordia sebestena

Bioassay-guided fractionation of an extract prepared from the fruits of Cordia sebestena led to the isolation of sebestenoids A-D (1-4). Their structures were elucidated on the basis of extensive NMR experiments and mass spectroscopic measurements. Compounds 1-4 exhibited moderate inhibition of the aspartic protease BACE1.     

Carbazole-containing arylcarboxamides as BACE1 inhibitors

β-Secretase (BACE1) is widely recognized as a prime drug target for the treatment of Alzheimer's disease (AD). In this Letter, we report the synthesis and the BACE1 inhibitory activity of novel, variously substituted N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-arylcarboxamides. The best results have been obtained with the introduction of a 4-OMe substituent (IC(50)=3.8 μM) or a 3,4-dichloro substituent (IC(50)=2.5 μM) in the amidic aromatic ring. The blood-brain barrier penetration predictions resulted to be promising for this type of compounds. To better understand the structure-activity relationships (SAR) of the new derivatives, a docking study procedure has been applied exploiting different conformational and ionic states of BACE1.     

Design, synthesis and biological evaluation of pyridine acyl sulfonamide derivatives as novel COX-2 inhibitors

A series of pyridine acyl sulfonamide derivatives (1-24) have been designed and synthesized and their biological activities were also evaluated as potential cyclooxygenase-2 (COX-2) inhibitors. Among all the compounds, compound 23 displayed the most potent COX-2 inhibitory activity with an IC(50) of 0.8 μM. Antitumor and anti-inflammatory assays indicated that compound 23 owned high antiproliferative activity against B16-F10, HepG2 and MCF-7 cancer cell lines as well as COX-2-derived prostaglandin E(2) (PGE(2)) inhibitory activity of murine macrophage RAW 264.7 cell line with IC(50) values of 2.8, 1.2, 1.8 and 0.15 μM, respectively. Docking simulation was performed to position compound 23 into the COX-2 active site to determine the probable binding model.     

PTP1B inhibitors: synthesis and evaluation of difluoro-methylenephosphonate bioisosteres on a sulfonamide scaffold

We have synthesized and evaluated a series of triaryl sulfonamide-based PTP1B inhibitors in which a difluoro-methylenephosphonate group of a potent lead has been replaced by potential bioisosteric replacements. Several mono- or di-charged compounds (8a, 8b, and 15a) were shown exhibit inhibitory activity in the low micromolar range, demonstrating the feasibility of using this approach in identifying non-phosphonate pTyr mimetics in a small molecular scaffold. These results also provide a useful indication of the relative effectiveness of these pTyr mimetics.     

Synthesis,characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitors

The development of 1,3,4,4a,5,10a-hexahydropyrano[3,4-b]chromene analogs as BACE1 inhibitors is described. Introduction of the spirocyclic pyranochromene scaffold yielded several advantages over previous generation cores, including increased potency, reduced efflux, and reduced CYP2D6 inhibition. Compound 13 (BACE1 IC₅₀ = 110 nM) demonstrated a reduction in CSF Aβ in wild type rats after a single dose.     

Design,synthesis, X-ray studies,and biological evaluation of novel BACE1 inhibitors with bicyclic isoxazoline carboxamides as the P3 ligand

We describe the design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors containing bicyclic isoxazoline carboxamides as the P3 ligand in combination with methyl cysteine, methylsulfonylalanine and Boc-amino alanine as P2 ligands. Inhibitor 3a displayed a BACE1 K_i value of 10.9?nM and EC₅₀ of 343?nM. The X-ray structure of 3a bound to the active site of BACE1 was determined at 2.85?Å resolution. The structure revealed that the major molecular interactions between BACE1 and the bicyclic tetrahydrofuranyl isoxazoline heterocycle are van der Waals in nature.     

Structure based design of iminohydantoin BACE1 inhibitors: identification of an orally available, centrally active BACE1 inhibitor

From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aβ following oral administration to rats. Herein we report SAR development in the S3 and F' subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.     

Design and synthesis of highly active Alzheimer's beta-secretase (BACE1) inhibitors, KMI-420 and KMI-429, with enhanced chemical stability

Recently, we reported potent and small-sized BACE1 inhibitors KMI-358 and KMI-370 in which the Glu residue is replaced by a beta-N-oxalyl-DAP (l-alpha,beta-diaminopropionyl) residue at the P(4) position. The beta-N-oxalyl-DAP group is important for enhancing BACE1 inhibitory activity, but these inhibitors isomerized to alpha-N-oxalyl-DAP derivatives in solvents. Hence, we used a tetrazole moiety as a bioisostere of the free carboxylic acid of the oxalyl group. KMI-420 and KMI-429, containing a tetrazole ring, showed improved stability and potent enzyme inhibitory activity.