RESUMO
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.
Assuntos
Ácidos Carboxílicos/química , Daptomicina/análogos & derivados , Daptomicina/síntese química , Ácido Aspártico/química , Técnicas de Química Sintética , Ácido Glutâmico/químicaRESUMO
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.
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Regulação Enzimológica da Expressão Gênica/fisiologia , PPAR alfa/metabolismo , Transdução de Sinais/fisiologia , Acetil-CoA Carboxilase/metabolismo , Animais , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hepatócitos , Humanos , Camundongos , Camundongos Obesos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
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.
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Convulsões/induzido quimicamente , Tiazóis/síntese química , Administração Oral , Animais , Expressão Gênica/efeitos dos fármacos , Infusões Intravenosas , Masculino , Miocárdio/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/efeitos adversos , Tiazóis/químicaRESUMO
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.
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Alcinos/síntese química , Hipoglicemiantes/síntese química , Tiazóis/síntese química , Acetil-CoA Carboxilase/genética , Alcinos/farmacocinética , Alcinos/farmacologia , Animais , Linhagem Celular , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Malonil Coenzima A/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologiaRESUMO
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.
Assuntos
Inibidores Enzimáticos/química , Peptídeo Sintases/antagonistas & inibidores , Peptídeo Sintases/química , Streptococcus pneumoniae/enzimologia , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/metabolismo , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Ressonância Magnética Nuclear Biomolecular , Peptídeo Sintases/metabolismo , Estrutura Terciária de Proteína , Alinhamento de Sequência , Homologia de Sequência , Especificidade por SubstratoRESUMO
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.
Assuntos
Vírus da Influenza A/enzimologia , Vírus da Influenza B/enzimologia , Neuraminidase/antagonistas & inibidores , Neuraminidase/química , Pirrolidinas/síntese química , Animais , Sítios de Ligação , Disponibilidade Biológica , Cristalografia por Raios X , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Adenosina Quinase/antagonistas & inibidores , Analgésicos/síntese química , Piridinas/síntese química , Pirimidinas/síntese química , Adenosina Quinase/química , Analgésicos/química , Analgésicos/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Medição da Dor , Fosforilação , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Química Farmacêutica/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Acetil-CoA Carboxilase/química , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Hipoglicemiantes/química , Concentração Inibidora 50 , Isoenzimas/química , Modelos Químicos , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Alcinos/síntese química , Alcinos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Acetil-CoA Carboxilase/genética , Fenômenos Químicos , Físico-Química , Humanos , Hidroxiureia/química , Isoxazóis/síntese química , Isoxazóis/farmacologia , Conformação Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Adenosina Trifosfatases/metabolismo , Antibacterianos/química , Proteínas de Bactérias/metabolismo , Química Farmacêutica/métodos , Haemophilus influenzae/metabolismo , Sequência de Aminoácidos , Animais , Linfócitos B/metabolismo , Desenho de Fármacos , Genoma Bacteriano , Genômica , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Dados de Sequência Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Éteres Fenílicos/química , Éteres Fenílicos/farmacologia , Acetil-CoA Carboxilase/metabolismo , Inibidores Enzimáticos/química , Estrutura Molecular , Éteres Fenílicos/síntese química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores Enzimáticos/química , Peptídeo Sintases/antagonistas & inibidores , Relação Estrutura-Atividade , Cristalização , Cristalografia por Raios X , Inibidores Enzimáticos/metabolismo , Concentração Inibidora 50 , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Peptídeo Sintases/química , Peptídeo Sintases/metabolismo , Especificidade por Substrato , Sulfonamidas/química , Sulfonamidas/metabolismoRESUMO
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.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologiaRESUMO
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.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos , Resistência a Múltiplos Medicamentos , Propanóis/síntese química , Propanóis/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Tilosina/análogos & derivados , Tilosina/síntese química , Tilosina/farmacologia , Antibacterianos/química , Antibacterianos/farmacocinética , Disponibilidade Biológica , Meia-Vida , Testes de Sensibilidade Microbiana , Propanóis/química , Relação Estrutura-Atividade , Tilosina/químicaRESUMO
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.
Assuntos
Adenosina Quinase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Pirimidinas/químicaRESUMO
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.
Assuntos
Antibacterianos/química , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/biossíntese , Naftiridinas/química , Inibidores da Síntese de Proteínas/química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Naftiridinas/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Vírus da Influenza A/enzimologia , Neuraminidase/antagonistas & inibidores , Neuraminidase/química , Aminas/química , Animais , Sítios de Ligação , Aves , Técnicas de Química Combinatória/métodos , Cristalização , Cristalografia por Raios X , Ciclopentanos/síntese química , Inibidores Enzimáticos/química , Ésteres , Modelos Moleculares , Nanotecnologia/métodos , Neuraminidase/isolamento & purificação , Pirrolidinas/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.