RESUMO
Pharmacological screening heavily relies on the reliability of compound libraries. To ensure the accuracy of screening results, fast and reliable quality control (QC) of these libraries is essential. While liquid chromatography (LC) with ultraviolet (UV) or mass spectrometry (MS) detection has been employed for molecule QC on small sample sets, the analytical throughput becomes a bottleneck when dealing with large libraries. Acoustic ejection mass spectrometry (AEMS) is a high-throughput analytical platform that covers a broad range of chemical structural space. In this study, we present the utilization of an AEMS system equipped with a high-resolution MS analyzer for high-throughput compound QC. To facilitate efficient data processing, which is a key challenge for such a high-throughput application, we introduce an automatic data processing toolkit that allows for the high-throughput assessment of the sample standards' quantitative and qualitative characteristics, including purity calculation with the background processing option. Moreover, the toolkit includes a module for quantitatively comparing spectral similarity with the reference library. Integrating the described high-resolution AEMS system with the data processing toolkit effectively eliminates the analytical bottleneck, enabling a rapid and reliable compound quality assessment of large-scale compound libraries.
RESUMO
The synthesis and in vivo pharmacokinetic profile of an analogue of cyclosporine is disclosed. An acyclic congener was also profiled in in vitro assays to compare cell permeability. The compounds possess similar calculated and measured molecular descriptors however have different behaviors in an RRCK assay to assess cell permeability.
Assuntos
Ciclosporina/farmacocinética , Oligopeptídeos/farmacocinética , Animais , Ciclosporina/administração & dosagem , Ciclosporina/química , Masculino , Conformação Molecular , Oligopeptídeos/administração & dosagem , Oligopeptídeos/química , Ratos , Ratos Wistar , EstereoisomerismoRESUMO
A visible-light-driven Minisci protocol that employs an inexpensive earth-abundant metal catalyst, decacarbonyldimanganese Mn2 (CO)10 , to generate alkyl radicals from alkyl iodides has been developed. This Minisci protocol is compatible with a wide array of sensitive functional groups, including oxetanes, sugar moieties, azetidines, tert-butyl carbamates (Boc-group), cyclobutanes, and spirocycles. The robustness of this protocol is demonstrated on the late-stage functionalization of complex nitrogen-containing drugs. Photophysical and DFT studies indicate a light-initiated chain reaction mechanism propagated by . Mn(CO)5 . The rate-limiting step is the iodine abstraction from an alkyl iodide by . Mn(CO)5 .
RESUMO
The chemokine receptor CXCR7 is an attractive target for a variety of diseases. While several small-molecule modulators of CXCR7 have been reported, peptidic macrocycles may provide advantages in terms of potency, selectivity, and reduced off-target activity. We produced a series of peptidic macrocycles that incorporate an N-linked peptoid functionality where the peptoid group enabled us to explore side-chain diversity well beyond that of natural amino acids. At the same time, theoretical calculations and experimental assays were used to track and reduce the polarity while closely monitoring the physicochemical properties. This strategy led to the discovery of macrocyclic peptide-peptoid hybrids with high CXCR7 binding affinities (Ki < 100 nM) and measurable passive permeability (Papp > 5 × 10-6 cm/s). Moreover, bioactive peptide 25 (Ki = 9 nM) achieved oral bioavailability of 18% in rats, which was commensurate with the observed plasma clearance values upon intravenous administration.
Assuntos
Peptídeos/química , Peptídeos/farmacologia , Peptoides/química , Peptoides/farmacologia , Receptores CXCR/agonistas , Receptores CXCR/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Cães , Humanos , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacocinética , Compostos Macrocíclicos/farmacologia , Células Madin Darby de Rim Canino , Masculino , Simulação de Acoplamento Molecular , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Peptoides/administração & dosagem , Peptoides/farmacocinética , Ratos , Ratos WistarRESUMO
Inhibition of the sodium-coupled citrate transporter (NaCT or SLC13A5) has been proposed as a new therapeutic approach for prevention and treatment of metabolic diseases. In a previous report, we discovered dicarboxylate 1a (PF-06649298) which inhibits the transport of citrate in in vitro and in vivo settings via a specific interaction with NaCT. Herein, we report the optimization of this series leading to 4a (PF-06761281), a more potent inhibitor with suitable in vivo pharmacokinetic profile for assessment of in vivo pharmacodynamics. Compound 4a was used to demonstrate dose-dependent inhibition of radioactive [(14)C]citrate uptake in liver and kidney in vivo, resulting in modest reductions in plasma glucose concentrations.
Assuntos
Citratos/metabolismo , Malatos/química , Malatos/farmacologia , Fenilbutiratos/química , Fenilbutiratos/farmacologia , Piridinas/química , Piridinas/farmacologia , Simportadores/antagonistas & inibidores , Animais , Transporte Biológico/efeitos dos fármacos , Glicemia/metabolismo , Citratos/farmacocinética , Relação Dose-Resposta a Droga , Células HEK293 , Hepatócitos/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Malatos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Estrutura Molecular , Fenilbutiratos/administração & dosagem , Piridinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Simportadores/metabolismoRESUMO
The effect of peptide-to-peptoid substitutions on the passive membrane permeability of an N-methylated cyclic hexapeptide is examined. In general, substitutions maintained permeability but increased conformational heterogeneity. Diversification with nonproteinogenic side chains increased permeability up to 3-fold. Additionally, the conformational impact of peptoid substitutions within a ß-turn are explored. Based on these results, the strategic incorporation of peptoid residues into cyclic peptides can maintain or improve cell permeability, while increasing access to diverse side-chain functionality.
Assuntos
Células Epiteliais/efeitos dos fármacos , Peptídeos/farmacologia , Permeabilidade/efeitos dos fármacos , Animais , Linhagem Celular , Cães , Células Epiteliais/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Simulação de Dinâmica Molecular , Peptídeos/química , Relação Estrutura-AtividadeRESUMO
Despite the prevalence of head-to-side chain threonine linkages in natural products, their incorporation has been underexplored in synthetic cyclic peptides. Herein we investigate a cyclic peptide scaffold able to undergo an N-O acyl rearrangement. Upon acylation of the amine with diverse carboxylic acids, the resulting cyclic depsipeptides displayed favorable cellular permeability and a conformation similar to the parent peptide. The rearrangement was found to be scaffold and conformation dependent as evidenced by molecular dynamics experiments.
Assuntos
Produtos Biológicos/síntese química , Depsipeptídeos/síntese química , Acilação , Sequência de Aminoácidos , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Depsipeptídeos/química , Depsipeptídeos/farmacologia , Conformação Molecular , Estrutura Molecular , Peptídeos/química , Peptídeos CíclicosRESUMO
A series of cyclic peptides were designed and prepared to investigate the physicochemical properties that affect oral bioavailabilty of this chemotype in rats. In particular, the ionization state of the peptide was examined by the incorporation of naturally occurring amino acid residues that are charged in differing regions of the gut. In addition, data was generated in a variety of in vitro assays and the usefulness of this data in predicting the subsequent oral bioavailability observed in the rat is discussed.