RESUMEN
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.
RESUMEN
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.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Imidazoles/química , Inhibidores de Proteasas/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Conformación Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Estructura Terciaria de ProteínaRESUMEN
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.
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Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico , Inhibidores Enzimáticos/farmacocinética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Dominio Catalítico , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Unión ProteicaRESUMEN
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.
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Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/química , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Inhibidores Enzimáticos/uso terapéutico , Humanos , Modelos Animales , Estructura MolecularAsunto(s)
Paladio/química , Fosfinas/química , Alquilación , Cinética , Estructura Molecular , Oxidación-Reducción , Estereoisomerismo , TermodinámicaRESUMEN
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.
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Enfermedad de Alzheimer/patología , Encéfalo/patología , Colorantes Fluorescentes , Microscopía Fluorescente/métodos , Técnicas de Sonda Molecular , Espectroscopía Infrarroja Corta/métodos , Animales , HumanosRESUMEN
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.
RESUMEN
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.
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Alquenos/química , Derivados del Benceno/química , Paladio/química , Catálisis , Cristalografía por Rayos X , Modelos MolecularesRESUMEN
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.