ABSTRACT
Modification of potent, selective metabotropic glutamate receptor 2 negative allosteric modulator (mGluR2 NAM) led to a series of analogues with excellent binding affinity, lipophilicity, and suitable physicochemical properties for a PET tracer with convenient chemical handles for incorporation of a 11C or 18F radiolabel. [11C]MK-8056 was synthesized and evaluated in vivo and demonstrated appropriate affinity, selectivity, and physicochemical properties to be used as a positron emission tomography tracer for mGluR2.
ABSTRACT
A small molecule inhibitor of beta-secretase with a unique binding mode has been developed. Crystallographic determination of the enzyme-inhibitor complex shows the catalytic aspartate residues in the active site are not engaged in inhibitor binding. This unprecedented binding mode in the field of aspartyl protease inhibition is described.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid , Enzyme Inhibitors/pharmacokinetics , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/metabolism , Catalytic Domain , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Protein BindingABSTRACT
During our ongoing efforts to develop a small molecule inhibitor targeting the beta-amyloid cleaving enzyme (BACE-1), we discovered a class of compounds bearing an aminoimidazole motif. Initial optimization led to potent compounds that have high Pgp efflux ratios. Crystal structure-aided design furnished conformationally constrained compounds that are both potent and have relatively low Pgp efflux ratios. Computational studies performed after these optimizations suggest that the introduction of the constraint enhances potency via additional hydrophobic interactions rather than conformational restriction.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Imidazoles/chemistry , Protease Inhibitors/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Amyloid Precursor Protein Secretases/metabolism , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Drug Design , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Molecular Conformation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Protein Structure, TertiaryABSTRACT
Over the last six years, numerous research groups in both academia and industry have synthesized inhibitors of beta-amyloid cleaving enzyme-1 (BACE-1) in the hope of developing a therapy to halt or even reverse the progression of Alzheimer's disease. While several compounds have been demonstrated to be potent in vitro inhibitors of BACE-1, only a small subset of these compounds are able to satisfy other practical considerations essential for the development of a preclinical drug candidate. These considerations include selectivity of the inhibitor toward BACE-1 over other enzymes, cellular activity, and in vivo activity in an animal model. This review will summarize the recent development of BACE-1 inhibitors with particular focus placed on inhibitors that address some of the requirements necessary for a practical drug candidate.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemistry , Alzheimer Disease/drug therapy , Animals , Enzyme Inhibitors/therapeutic use , Humans , Models, Animal , Molecular StructureSubject(s)
Palladium/chemistry , Phosphines/chemistry , Alkylation , Kinetics , Molecular Structure , Oxidation-Reduction , Stereoisomerism , ThermodynamicsABSTRACT
PURPOSE: Near-infrared fluorescent probes for amyloid-beta (Abeta) are an exciting option for molecular imaging in Alzheimer's disease research and may translate to clinical diagnostics. However, Abeta-targeted optical probes often suffer from poor specificity and slow clearance from the brain. We are designing smart optical probes that emit characteristic fluorescence signal only when bound to Abeta. METHODS: We synthesized a family of dyes and tested Abeta-binding sensitivity with fluorescence spectroscopy and tissue-staining. RESULTS: Select compounds exhibited Abeta-dependent changes in fluorescence quantum yield, lifetime, and emission spectra that may be imaged microscopically or in vivo using new lifetime and spectral fluorescence imaging techniques. CONCLUSION: Smart optical probes that turn on when bound to Abeta will improve amyloid detection and may enable quantitative molecular imaging in vivo.
Subject(s)
Alzheimer Disease/pathology , Brain/pathology , Fluorescent Dyes , Microscopy, Fluorescence/methods , Molecular Probe Techniques , Spectroscopy, Near-Infrared/methods , Animals , HumansABSTRACT
The synthesis and resolution of a new planar-chiral Lewis acid complex is described. The compound is applied to asymmetric Mukaiyama aldol reactions, leading to the formation of the desired product with good stereoselectivity. The sense of stereoselection is as predicted by the design, which exploits the ability of the Lewis acid to simultaneously serve as a sigma and a pi acceptor. Mechanistic observations are consistent with rate-determining formation of an aldehyde-Lewis acid complex, followed by rapid nucleophilic addition.
ABSTRACT
This communication describes a series of studies directed at obtaining a better understanding of the Heck reaction. For the first time, the postulated palladium-hydride intermediate (L2PdHX) in the catalytic cycle of the Heck arylation has been identified. In addition, this study establishes that the base-mediated Pd(0)-regeneration step (L2PdHX --> PdL2) of the cycle can be kinetically slow and thermodynamically unfavorable and that the process is remarkably sensitive to the structure of L (PCy3 vs P(t-Bu)3). Finally, this investigation demonstrates that, for certain catalyst systems, slow rates of Heck arylation can be correlated with reluctant reductive elimination of L2PdHX, furnishing a possible rationalization for Brønsted-base (Cs2CO3 vs Cy2NMe) and ligand (PCy3 vs P(t-Bu)3) effects that have been observed.
Subject(s)
Alkenes/chemistry , Benzene Derivatives/chemistry , Palladium/chemistry , Catalysis , Crystallography, X-Ray , Models, MolecularABSTRACT
The Suzuki reaction is an exceptionally useful cross-coupling process that has been widely applied in synthetic chemistry, and boronic acids are, by far, the most commonly employed coupling partner. To date, however, no versatile method has been developed for cross-coupling boronic acids with unactivated alkyl (as opposed to aryl or vinyl) electrophiles. This report describes a catalyst system that achieves this objective at room temperature. On the mechanistic side, this study demonstrates that Pd(P(t-Bu)2Me)2 undergoes oxidative addition under surprisingly mild conditions (0 degrees C). The resulting adduct is sufficiently stable toward beta-hydride elimination that it can be structurally characterized, and it is a chemically competent intermediate in the cross-coupling process.