RESUMEN
Herein we report a direct and efficient method for the synthesis of four new carboxylate-isostere analogs of daptomycin. The side chain carboxylic acid moieties of the aspartic acids (Asp-3, Asp-7 and Asp-9) and ß-methyl glutamic acid (MeGlu-12) were all converted into the corresponding carboxylate isosteres using direct synthetic procedures. The present study also describes an esterification protocol to overcome the possible backbone cyclization of the activated side chain carboxylic acid group of either Asp or Glu onto the backbone amide.
Asunto(s)
Ácidos Carboxílicos/química , Daptomicina/análogos & derivados , Daptomicina/síntesis química , Ácido Aspártico/química , Técnicas de Química Sintética , Ácido Glutámico/químicaRESUMEN
Acetyl CoA carboxylase (ACC) 2, which catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, has been identified as a potential target for type 2 diabetes and obesity. Small-molecule inhibitors of ACC2 would be expected to reduce de novo lipid synthesis and increase lipid oxidation. Treatment of ob/ob mice with compound A-908292 (S) ({(S)-3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methyl-prop-2-ynyl}-carbamic acid methyl ester), a small-molecule inhibitor with an IC(50) of 23 nM against ACC2, resulted in a reduction of serum glucose and triglyceride levels. However, compound A-875400 (R) ({(R)-3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methyl-prop-2-ynyl}-carbamic acid methyl ester), an inactive enantiomer of A-908292 (S) with approximately 50-fold less activity against ACC2, also caused a similar reduction in glucose and triglycerides, suggesting that the glucose-lowering effects in ob/ob mice may be mediated by other metabolic pathways independent of ACC2 inhibition. To characterize the pharmacological activity of these experimental compounds at a transcriptional level, rats were orally dosed for 3 days with either A-908292 (S) or A-875400 (R), and gene expression analysis was performed. Gene expression analysis of livers showed that treatment with A-908292 (S) or A-875400 (R) resulted in gene expression profiles highly similar to known peroxisome proliferator-activated receptor (PPAR)-alpha activators. The results suggest that, in vivo, both A-908292 (S) and A-875400 (R) stimulated the PPAR-alpha-dependent signaling pathway. These results were further supported by both an in vitro genomic evaluation using rat hepatocytes and immunohistochemical evaluation using 70-kDa peroxisomal membrane protein. Overall, the gene expression analysis suggests a plausible mechanism for the similar pharmacological findings with active and inactive enantiomers of an ACC2 inhibitor.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Regulación Enzimológica de la Expresión Génica/fisiología , PPAR alfa/metabolismo , Transducción de Señal/fisiología , Acetil-CoA Carboxilasa/metabolismo , Animales , Inhibidores Enzimáticos/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hepatocitos , Humanos , Ratones , Ratones Obesos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
A preliminary safety evaluation of ACC2 inhibitor 1-(S) revealed serious neurological and cardiovascular liabilities of this chemotype. A systematic structure-toxicity relationship study identified the alkyne linker as the key motif responsible for these adverse effects. Toxicogenomic studies in rats showed that 1-(R) and 1-(S) induced gene expression patterns similar to that seen with several known cardiotoxic agents such as doxorubicin. Replacement of the alkyne with alternative linker groups led to a new series of ACC inhibitors with drastically improved cardiovascular and neurological profiles.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Convulsiones/inducido químicamente , Tiazoles/síntesis química , Administración Oral , Animales , Expresión Génica/efectos de los fármacos , Infusiones Intravenosas , Masculino , Miocardio/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/efectos adversos , Tiazoles/químicaRESUMEN
A structurally novel acetyl-CoA carboxylase (ACC) inhibitor is identified from high-throughput screening. A preliminary structure-activity relationship study led to the discovery of potent dual ACC1/ACC2 and ACC2 selective inhibitors against human recombinant ACC1 and ACC2. Selective ACC2 inhibitors exhibited IC50<20 nM and >1000-fold selectivity against ACC1. (S)-Enantiomer 9p exhibited high ACC2 activity and lowered muscle malonyl-CoA dose-dependently in acute rodent studies, whereas (R)-enantiomer 9o was weak and had no effect on the malonyl-CoA level.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Alquinos/síntesis química , Hipoglucemiantes/síntesis química , Tiazoles/síntesis química , Acetil-CoA Carboxilasa/genética , Alquinos/farmacocinética , Alquinos/farmacología , Animales , Línea Celular , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Técnicas In Vitro , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Malonil Coenzima A/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
In a broad genomics analysis to find novel protein targets for antibiotic discovery, MurF was identified as an essential gene product for Streptococcus pneumonia that catalyzes a critical reaction in the biosynthesis of the peptidoglycan in the formation of the cell wall. Lacking close relatives in mammalian biology, MurF presents attractive characteristics as a potential drug target. Initial screening of the Abbott small-molecule compound collection identified several compounds for further validation as pharmaceutical leads. Here we report the integrated efforts of NMR and X-ray crystallography, which reveal the multidomain structure of a MurF-inhibitor complex in a compact conformation that differs dramatically from related structures. The lead molecule is bound in the substrate-binding region and induces domain closure, suggestive of the domain arrangement for the as yet unobserved transition state conformation for MurF enzymes. The results form a basis for directed optimization of the compound lead by structure-based design to explore the suitability of MurF as a pharmaceutical target.
Asunto(s)
Inhibidores Enzimáticos/química , Péptido Sintasas/antagonistas & inhibidores , Péptido Sintasas/química , Streptococcus pneumoniae/enzimología , Secuencia de Aminoácidos , Sitios de Unión , Cristalografía por Rayos X , Inhibidores Enzimáticos/metabolismo , Ligandos , Modelos Moleculares , Datos de Secuencia Molecular , Resonancia Magnética Nuclear Biomolecular , Péptido Sintasas/metabolismo , Estructura Terciaria de Proteína , Alineación de Secuencia , Homología de Secuencia , Especificidad por SustratoRESUMEN
The structure-activity relationship (SAR) of a novel hydrophobic binding interaction within a subsite of the influenza neuraminidase (NA) active site was characterized and optimized for a series of trisubstituted pyrrolidine inhibitors modified at the 4-position. Previously, potent inhibitors have targeted this subsite with hydrophilic substituents such as amines and guanidines. Inhibitor-bound crystal structures revealed that hydrophobic substituents with sp(2) hybridization could achieve optimal interactions by virtue of a low-energy binding conformation and favorable pi-stacking interactions with the residue Glu119. From a lead methyl ester, investigation of five-membered heteroaromatic substituents at C-4 produced a 3-pyrazolyl analogue that improved activity by making a targeted hydrogen bond with Trp178. The SAR of substituted vinyl substituents at C-4 produced a Z-propenyl analogue with improved activity over the lead methyl ester. The C-1 ethyl ester prodrugs of the substituted C-4 vinyl analogues gave compounds with excellent oral bioavailability (F > 60%) when dosed in rat.
Asunto(s)
Virus de la Influenza A/enzimología , Virus de la Influenza B/enzimología , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/química , Pirrolidinas/síntesis química , Animales , Sitios de Unión , Disponibilidad Biológica , Cristalografía por Rayos X , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity relationship of a series of 5,6,7-trisubstituted 4-aminopyrido[2,3-d]pyrimidines as novel nonnucleoside adenosine kinase inhibitors is described. A variety of alkyl, aryl, and heteroaryl substituents were found to be tolerated at the C5, C6, and C7 positions of the pyridopyrimidine core. These studies have led to the identification of analogues that are potent inhibitors of adenosine kinase with in vivo analgesic activity.
Asunto(s)
Adenosina Quinasa/antagonistas & inhibidores , Analgésicos/síntesis química , Piridinas/síntesis química , Pirimidinas/síntesis química , Adenosina Quinasa/química , Analgésicos/química , Analgésicos/farmacología , Animales , Línea Celular Tumoral , Humanos , Ratones , Dimensión del Dolor , Fosforilación , Piridinas/química , Piridinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The structure-activity relationship study focused on the polar region of the HTS hit A-80040 (1) producing several series of potent and selective ACC2 inhibitors. The SAR suggests a compact lipophilic pocket that does not tolerate polar and ionic groups. Replacement of the hydroxyurea group with isoxazoles improves ACC2 selectivity while maintaining potency. Variations at the propargylic site of 11a reduce ACC2 potency.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Alquinos/síntesis química , Alquinos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Tiazoles/síntesis química , Tiazoles/farmacología , Acetil-CoA Carboxilasa/genética , Fenómenos Químicos , Química Física , Humanos , Hidroxiurea/química , Isoxazoles/síntesis química , Isoxazoles/farmacología , Conformación Molecular , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
A phenyl ring substitution strategy was employed to optimize the ACC2 potency and selectivity profiles of a recently discovered phenoxy thiazolyl series of acetyl-CoA carboxylase inhibitors. Ring substituents were shown to dramatically affect isozyme selectivity. Modifications that generally impart high levels of ACC2 selectivity (>3000-fold) while maintaining excellent ACC2 potency (IC50s approximately 9-20 nM) were identified.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Química Farmacéutica/métodos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Acetil-CoA Carboxilasa/química , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Hipoglucemiantes/química , Concentración 50 Inhibidora , Isoenzimas/química , Modelos Químicos , Conformación Molecular , Relación Estructura-ActividadRESUMEN
As part of a fully integrated and comprehensive strategy to discover novel antibacterial agents, NMR- and mass spectrometry-based affinity selection screens were performed to identify compounds that bind to protein targets uniquely found in bacteria and encoded by genes essential for microbial viability. A biphenyl acid lead series emerged from an NMR-based screen with the Haemophilus influenzae protein HI0065, a member of a family of probable ATP-binding proteins found exclusively in eubacteria. The structure-activity relationships developed around the NMR-derived biphenyl acid lead were consistent with on-target antibacterial activity as the Staphylococcus aureus antibacterial activity of the series correlated extremely well with binding affinity to HI0065, while the correlation of binding affinity with B-cell cytotoxicity was relatively poor. Although further studies are needed to conclusively establish the mode of action of the biphenyl series, these compounds represent novel leads that can serve as the basis for the development of novel antibacterial agents that appear to work via an unprecedented mechanism of action. Overall, these results support the genomics-driven hypothesis that targeting bacterial essential gene products that are not present in eukaryotic cells can identify novel antibacterial agents.
Asunto(s)
Adenosina Trifosfatasas/metabolismo , Antibacterianos/química , Proteínas Bacterianas/metabolismo , Química Farmacéutica/métodos , Haemophilus influenzae/metabolismo , Secuencia de Aminoácidos , Animales , Linfocitos B/metabolismo , Diseño de Fármacos , Genoma Bacteriano , Genómica , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Datos de Secuencia Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
Structure-activity relationships for a recently discovered thiazolyl phenyl ether series of acetyl-CoA carboxylase (ACC) inhibitors were investigated. Preliminary efforts to optimize the series through modification of the distal aryl ether moiety of the lead scaffold resulted in the identification of compounds exhibiting low-nanomolar potency and isozyme-selective ACC2 activity.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Éteres Fenílicos/química , Éteres Fenílicos/farmacología , Acetil-CoA Carboxilasa/metabolismo , Inhibidores Enzimáticos/química , Estructura Molecular , Éteres Fenílicos/síntesis química , Relación Estructura-ActividadRESUMEN
The D-Ala-D-Ala adding enzyme (MurF) from Streptococcus pneumoniae catalyzes the ATP-dependent formation of the UDP-MurNAc-pentapeptide, a critical component of the bacterial cell wall. MurF is a potential target for antibacterial design because it is unique to bacteria and performs an essential non-redundant function in the bacterial cell. The recent discovery and subsequent cocrystal structure determination of MurF in complex with a new class of inhibitors served as a catalyst to begin a medicinal chemistry program aimed at improving their potency. We report here a multidisciplinary approach to this effort that allowed for rapid generation of cocrystal structures, thereby providing the crystallographic information critical for driving the inhibitor optimization process. This effort resulted in the discovery of low-nanomolar inhibitors of this bacterial enzyme.
Asunto(s)
Inhibidores Enzimáticos/química , Péptido Sintasas/antagonistas & inhibidores , Relación Estructura-Actividad , Cristalización , Cristalografía por Rayos X , Inhibidores Enzimáticos/metabolismo , Concentración 50 Inhibidora , Ligandos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Péptido Sintasas/química , Péptido Sintasas/metabolismo , Especificidad por Sustrato , Sulfonamidas/química , Sulfonamidas/metabolismoRESUMEN
A novel series of 6-O-arylpropargyl diazalides was synthesized and evaluated for their antibacterial activity. Members of this series exhibited potent activity against erythromycin-resistant respiratory tract pathogens.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Farmacorresistencia Microbiana , Resistencia a Múltiples Medicamentos , Propanoles/síntesis química , Propanoles/farmacología , Streptococcus pneumoniae/efectos de los fármacos , Tilosina/análogos & derivados , Tilosina/síntesis química , Tilosina/farmacología , Antibacterianos/química , Antibacterianos/farmacocinética , Disponibilidad Biológica , Semivida , Pruebas de Sensibilidad Microbiana , Propanoles/química , Relación Estructura-Actividad , Tilosina/químicaRESUMEN
A series of 5-methoxy- and 5-hydroxy-6-fluoro-1,8-naphthyridone-3-carboxylic acid derivatives were prepared and evaluated for cell-free bacterial protein synthesis inhibition and whole cell antibacterial activity. When compared to the analogous 5-hydrogen compounds, the presence of the 5-OH group negatively affects biochemical potency. However, a tolerance of the 5-methoxy group is indicated. Only moderate whole cell antibacterial activity is seen, but this could be due to poor cellular penetration. Because only a few 7-position variants were made for this study, further investigation into this novel series combining a broader range of 7-amino derivatives with these 5-position modifications is warranted.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacologíaRESUMEN
The synthesis and structure-activity relationship of a series of 6,7-disubstituted 4-aminopyrido[2,3-d]pyrimidines as novel non-nucleoside adenosine kinase inhibitors is described. A variety of substituents, primarily aryl, at the C6 and C7 positions of the pyridopyrimidine core were found to yield analogues that are potent inhibitors of adenosine kinase. In contrast to the 5,7-disubstituted and 5,6,7-trisubstituted pyridopyrimidine series, these analogues exhibited only modest potency to inhibit AK in intact cells.
Asunto(s)
Adenosina Quinasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Pirimidinas/químicaRESUMEN
A novel class of MurF inhibitors was discovered and structure-activity relationship studies have led to several potent compounds with IC(50)=22 approximately 70 nM. Unfortunately, none of these potent MurF inhibitors exhibited significant antibacterial activity even in the presence of bacterial cell permeabilizers.
Asunto(s)
Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Péptido Sintasas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Péptido Sintasas/metabolismo , Peptidoglicano/biosíntesis , Relación Estructura-ActividadRESUMEN
Combinatorial and structure-based medicinal chemistry strategies were used together to advance a lead compound with an activity of K(i) = 58 microM via a potency enhancement of >70 000-fold to an analogue with an activity of K(i) = 0.8 nM against influenza neuraminidase (A/Tokyo/67). Lead optimization was initiated using molecular modeling and combinatorial chemistry. Protein crystal structures revealed that inconsistent structure-activity relationship (SAR) data resulted from different binding orientations of the inhibitor core five-membered rings from one series to another. Binding modes for a series of compounds showed up to a 180 degrees variation in orientation of the five-membered ring within the active site. Potent analogues were only achieved with chemical series that were observed to bind in the same orientation and yielded consistent SAR. In one series, consistent binding was obtained by an unprecedented occupation of a negatively charged binding pocket by a neutral methyl ester unit. The structural rationale for this novel SAR variation, based on protein crystallographic data, is given.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Virus de la Influenza A/enzimología , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/química , Aminas/química , Animales , Sitios de Unión , Aves , Técnicas Químicas Combinatorias/métodos , Cristalización , Cristalografía por Rayos X , Ciclopentanos/síntesis química , Inhibidores Enzimáticos/química , Ésteres , Modelos Moleculares , Nanotecnología/métodos , Neuraminidasa/aislamiento & purificación , Pirrolidinas/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Structure-activity relationships for a recently discovered novel ribosome inhibitor (NRI) class of antibacterials were investigated. Preliminary efforts to optimize protein synthesis inhibitory activity of the series through modification of positions 3 and 4 of the naphthyridone lead template resulted in the identification of several biochemically potent analogues. A lack of corresponding whole cell antibacterial activity is thought to be a consequence of poor cellular penetration as evidenced by the enhancement of activity observed for a lead analogue tested in the presence of a cell permeabilizing agent.