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1.
Angew Chem Int Ed Engl ; 63(19): e202400509, 2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38419352

RESUMEN

In 2001, our curiosity to understand the stereochemistry of C-H metalation with Pd prompted our first studies in Pd(II)-catalyzed asymmetric C-H activation (RSC Research appointment: 020 7451 2545, Grant: RG 36873, Dec. 2002). We identified four central challenges: 1. poor reactivity of simple Pd salts with native substrates; 2. few strategies to control site selectivity for remote C-H bonds; 3. the lack of chiral catalysts to achieve enantioselectivity via asymmetric C-H metalation, and 4. low practicality due to limited coupling partner scope and the use of specialized oxidants. These challenges necessitated new strategies in catalyst and reaction development. For reactivity, we developed approaches to enhance substrate-catalyst affinity together with novel bifunctional ligands which participate in and accelerate the C-H cleavage step. For site-selectivity, we introduced the concept of systematically modulating the distance and geometry between a directing template, catalyst, and substrate to selectively access remote C-H bonds. For enantioselectivity, we devised predictable stereomodels for catalyst-controlled enantioselective C-H activation based on the participation of bifunctional ligands. Finally, for practicality, we have developed varied catalytic manifolds for Pd(II) to accommodate diverse coupling partners while employing practical oxidants such as simple peroxides. These advances have culminated in numerous C-H activation reactions, setting the stage for broad industrial applications.

2.
Nature ; 540(7633): 458-461, 2016 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-27926736

RESUMEN

CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer. These disease associations have motivated numerous preclinical studies and clinical trials (see http://www.clinicaltrials.gov) in search of therapies that target the CCR2-chemokine axis. To aid drug discovery efforts, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive G-protein-coupled receptor structures solved so far. Like other protein-protein interactions, receptor-chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.


Asunto(s)
Pirrolidinonas/química , Pirrolidinonas/farmacología , Quinazolinas/química , Quinazolinas/farmacología , Receptores CCR2/antagonistas & inhibidores , Receptores CCR2/química , Sitio Alostérico/efectos de los fármacos , Sitios de Unión , Quimiocinas CC/metabolismo , Cristalografía por Rayos X , Diseño de Fármacos , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Humanos , Ligandos , Modelos Moleculares
3.
J Am Chem Soc ; 143(13): 5141-5149, 2021 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-33783207

RESUMEN

Ligand-induced protein degradation has emerged as a compelling approach to promote the targeted elimination of proteins from cells by directing these proteins to the ubiquitin-proteasome machinery. So far, only a limited number of E3 ligases have been found to support ligand-induced protein degradation, reflecting a dearth of E3-binding compounds for proteolysis-targeting chimera (PROTAC) design. Here, we describe a functional screening strategy performed with a focused library of candidate electrophilic PROTACs to discover bifunctional compounds that degrade proteins in human cells by covalently engaging E3 ligases. Mechanistic studies revealed that the electrophilic PROTACs act through modifying specific cysteines in DCAF11, a poorly characterized E3 ligase substrate adaptor. We further show that DCAF11-directed electrophilic PROTACs can degrade multiple endogenous proteins, including FBKP12 and the androgen receptor, in human prostate cancer cells. Our findings designate DCAF11 as an E3 ligase capable of supporting ligand-induced protein degradation via electrophilic PROTACs.


Asunto(s)
Complejos de Ubiquitina-Proteína Ligasa/fisiología , Línea Celular Tumoral , Humanos , Masculino , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Receptores Androgénicos/metabolismo , Ubiquitina/metabolismo , Complejos de Ubiquitina-Proteína Ligasa/metabolismo
4.
Chemistry ; 22(21): 7059-62, 2016 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-26991450

RESUMEN

A Pd-catalyzed/N-heterocycle-directed C(sp(3) )-H olefination has been developed. The monoprotected amino acid ligand (MPAA) is found to significantly promote Pd-catalyzed C(sp(3) )-H olefination for the first time. Cu(OAc)2 instead of Ag(+) salts are used as the terminal oxidant. This reaction provides a useful method for the synthesis of alkylated pyrazoles.


Asunto(s)
Alquenos/química , Pirazoles/química , Alquenos/síntesis química , Alquilación , Catálisis , Ligandos , Oxidantes/química , Paladio/química , Pirazoles/síntesis química
5.
Chemistry ; 22(14): 4748-52, 2016 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-26841330

RESUMEN

Pd(II)-catalyzed C(sp(3))-H arylation of saturated heterocycles with a wide range of aryl iodides is enabled by an N-heterocyclic carbene (NHC) ligand. A C(sp(3))-H insertion step by the Pd(II)/NHC complex in the absence of ArI is demonstrated experimentally for the first time. Experimental data suggests that the previously established NHC-mediated Pd(0)/Pd(II) catalytic manifold does not operate in this reaction. This transformation provides a new approach for diversifying pharmaceutically relevant piperidine and tetrahydropyran ring systems.


Asunto(s)
Metano/análogos & derivados , Piperidinas/química , Piranos/química , Catálisis , Ligandos , Metano/química , Estructura Molecular
6.
Bioorg Med Chem Lett ; 25(6): 1338-42, 2015 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-25677667
7.
Angew Chem Int Ed Engl ; 54(8): 2501-4, 2015 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-25641121

RESUMEN

A sequential triple C-H activation reaction directed by a pyrazole and an amide group leads to the well-controlled construction of sterically congested dihydrobenzo[e]indazole derivatives. This cascade reaction demonstrates that the often problematic competing C-H activation pathways in the presence of multiple directing groups can be harvested by design to improve step economy in synthesis. Pyrazole as a relatively weak coordinating group is shown to direct Csp3-H activation for the first time.


Asunto(s)
Pirazoles/química , Carbono/química , Catálisis , Hidrógeno/química , Paladio , Pirazoles/síntesis química
8.
Bioorg Med Chem Lett ; 24(1): 204-8, 2014 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-24332488

RESUMEN

HSP90 continues to be a target of interest for neurodegeneration indications. Selective knockdown of the HSP90 cytosolic isoforms α and ß is sufficient to reduce mutant huntingtin protein levels in vitro. Chemotype-dependent binding conformations of HSP90α/ß appear to strongly influence isoform selectivity. The rational design of HSP90α/ß inhibitors selective versus the mitochondrial (TRAP1) and endoplasmic reticulum (GRP94) isoforms offers a potential mitigating strategy for mechanism-based toxicities. Better tolerated HSP90 inhibitors would be attractive for targeting chronic neurodegenerative diseases such as Huntington's disease.


Asunto(s)
Diseño de Fármacos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Enfermedades Neurodegenerativas/tratamiento farmacológico , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Isoformas de Proteínas/antagonistas & inhibidores
9.
Bioorg Med Chem Lett ; 24(9): 2177-81, 2014 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-24685546

RESUMEN

A series of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV were identified and optimized to mid-to-low nanomolar potency against a variety of bacteria. However, in spite of seemingly adequate exposure achieved upon IV administration, the in vivo efficacy of the early lead compounds was limited by high levels of binding to serum proteins. To overcome this limitation, targeted serum shift prediction models were generated for each subclass of interest and were applied to the design of prospective analogs. As a result, numerous compounds with comparable antibacterial potency and reduced protein binding were generated. These efforts culminated in the synthesis of compound 10, a potent inhibitor with low serum shift that demonstrated greatly improved in vivo efficacy in two distinct rat infection models.


Asunto(s)
Antibacterianos/sangre , Bacterias/enzimología , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/antagonistas & inhibidores , Inhibidores de Topoisomerasa II/sangre , Animales , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/enzimología , Infecciones Bacterianas/microbiología , Proteínas Sanguíneas/metabolismo , Topoisomerasa de ADN IV/metabolismo , Humanos , Ratas , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/metabolismo , Inhibidores de Topoisomerasa II/farmacología
10.
Bioorg Med Chem Lett ; 24(15): 3398-402, 2014 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-24939756

RESUMEN

Extensive phase II metabolism of an advanced PKCε inhibitor resulted in sub-optimal pharmacokinetics in rat marked by elevated clearance. Synthesis of the O-glucuronide metabolite as a standard was followed by three distinct strategies to specifically temper phase II metabolic degradation of the parent molecule. In this study, it was determined that the introduction of proximal polarity to the primary alcohol generally curbed O-glucuronidation and improved PK and physical chemical properties while maintaining potency against the target. Utilization of a Jacobsen hydrolytic kinetic resolution to obtain optically enriched final compounds is also discussed.


Asunto(s)
Glucurónidos/farmacología , Proteína Quinasa C-epsilon/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Animales , Perros , Relación Dosis-Respuesta a Droga , Glucurónidos/química , Glucurónidos/metabolismo , Estructura Molecular , Proteína Quinasa C-epsilon/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
11.
Mol Pharmacol ; 84(4): 551-61, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23877010

RESUMEN

The chemokine receptor CCR2 is a G protein-coupled receptor that is activated primarily by the endogenous CC chemokine ligand 2 (CCL2). Many different small-molecule antagonists have been developed to inhibit this receptor, as it is involved in a variety of diseases characterized by chronic inflammation. Unfortunately, all these antagonists lack clinical efficacy, and therefore a better understanding of their mechanism of action is warranted. In this study, we examined the pharmacological properties of small-molecule CCR2 antagonists in radioligand binding and functional assays. Six structurally different antagonists were selected for this study, all of which displaced the endogenous agonist (125)I-CCL2 from CCR2 with nanomolar affinity. Two of these antagonists, INCB3344 [N-(2-(((3S,4S)-1-((1r,4S)-4-(benzo[d][1,3]dioxol-5-yl)-4-hydroxycyclohexyl)-4-ethoxypyrrolidin-3-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)benzamide] and CCR2-RA, were radiolabeled to study the binding site in greater detail. We discovered that [(3)H]INCB3344 and [(3)H]CCR2-RA bind to distinct binding sites at CCR2, the latter being the first allosteric radioligand for CCR2. Besides the binding properties of the antagonists, we examined CCR2 inhibition in multiple functional assays, including a novel label-free whole-cell assay. INCB3344 competitively inhibited CCL2-induced G protein activation, whereas CCR2-RA showed a noncompetitive or allosteric mode of inhibition. These findings demonstrated that the CCR2 antagonists examined in this study can be classified into two groups with different binding sites and thereby different modes of inhibition. We have provided further insights in CCR2 antagonism, and these insights are important for the development of novel CCR2 inhibitors.


Asunto(s)
Pirrolidinas/metabolismo , Receptores CCR2/antagonistas & inhibidores , Receptores CCR2/metabolismo , Sitios de Unión/fisiología , Línea Celular , Quimiocina CCL2/metabolismo , Quimiocina CCL2/farmacología , Quimiocinas/metabolismo , Quimiocinas/farmacología , Humanos , Unión Proteica/fisiología , Pirrolidinas/farmacología , Receptores CCR2/agonistas
12.
J Org Chem ; 78(2): 780-5, 2013 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-23252964

RESUMEN

Efforts to substitute the cyclopropane ring in a series of aryl cyclopropylnitriles led to the discovery of an operationally simple one-pot method for Knoevenagel condensation and subsequent Corey-Chaykovsky cyclopropanation giving diastereomerically pure products as a racemic mixture of enantiomers. Method development and results for variably substituted aryl acetonitriles and aldehydes in the reaction are reported. A concise synthesis of (±)-bicifadine in two steps is provided to demonstrate the utility of the method.


Asunto(s)
Aldehídos/química , Ciclopropanos/química , Nitrilos/química , Estructura Molecular , Estereoisomerismo
13.
Bioorg Med Chem Lett ; 20(9): 2828-31, 2010 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-20356737

RESUMEN

Bacterial DNA gyrase is an attractive target for the investigation of new antibacterial agents. Inhibitors of the GyrB subunit, which contains the ATP-binding site, are described in this communication. Novel, substituted 5-(1H-pyrazol-3-yl)thiazole compounds were identified as inhibitors of bacterial gyrase. Structure-guided optimization led to greater enzymatic potency and moderate antibacterial potency. Data are presented for the demonstration of selective enzyme inhibition of Escherichia coli GyrB over Staphylococcus aureus GyrB.


Asunto(s)
Antibacterianos/química , Inhibidores Enzimáticos/química , Tiazoles/química , Inhibidores de Topoisomerasa II , Antibacterianos/síntesis química , Antibacterianos/farmacología , Sitios de Unión , Cristalografía por Rayos X , Girasa de ADN/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacología
14.
Sci Rep ; 7(1): 52, 2017 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-28246398

RESUMEN

CC Chemokine Receptor 2 (CCR2) and its endogenous ligand CCL2 are involved in a number of diseases, including atherosclerosis. Several CCR2 antagonists have been developed as potential therapeutic agents, however their in vivo clinical efficacy was limited. In this report, we aimed to determine whether 15a, an antagonist with a long residence time on the human CCR2, is effective in inhibiting the development of atherosclerosis in a mouse disease model. First, radioligand binding assays were performed to determine affinity and binding kinetics of 15a on murine CCR2. To assess the in vivo efficacy, western-type diet fed apoE-/- mice were treated daily with 15a or vehicle as control. Treatment with 15a reduced the amount of circulating CCR2+ monocytes and the size of the atherosclerotic plaques in both the carotid artery and the aortic root. We then showed that the long pharmacokinetic half-life of 15a combined with the high drug concentrations ensured prolonged CCR2 occupancy. These data render 15a a promising compound for drug development and confirms high receptor occupancy as a key parameter when targeting chemokine receptors.


Asunto(s)
Apolipoproteínas E/genética , Aterosclerosis/tratamiento farmacológico , Ciclopentanos/farmacología , Isoquinolinas/farmacología , Receptores CCR2/antagonistas & inhibidores , Animales , Aorta/efectos de los fármacos , Aorta/patología , Apolipoproteínas E/deficiencia , Aterosclerosis/genética , Aterosclerosis/patología , Células CHO , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/patología , Cricetulus , Ciclopentanos/farmacocinética , Dieta Aterogénica , Modelos Animales de Enfermedad , Isoquinolinas/farmacocinética , Masculino , Ratones , Monocitos/metabolismo , Monocitos/patología , Receptores CCR2/metabolismo
15.
Org Lett ; 17(10): 2362-5, 2015 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-25915436

RESUMEN

A radical mediated C-H functionalization of 3,6-dichloropyridazine using primary alcohols, t-BuOOH, and TiCl3 to access alkoxy pyridazines is described. This transformation is conducted open to air and on gram scale. A subsequent cyclization step can then be employed to efficiently access diversely substituted tetrahydropyridopyridazines with multiple functional handles.


Asunto(s)
Radicales Libres/química , Piridazinas/síntesis química , Piridinas/síntesis química , Ciclización , Estructura Molecular , Piridazinas/química , Piridinas/química
16.
ChemMedChem ; 10(7): 1249-58, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26033831

RESUMEN

Animal models suggest that the chemokine ligand 2/CC-chemokine receptor 2 (CCL2/CCR2) axis plays an important role in the development of inflammatory diseases. However, CCR2 antagonists have failed in clinical trials because of a lack of efficacy. We previously described a new approach for the design of CCR2 antagonists by the use of structure-kinetics relationships (SKRs). Herein we report new findings on the structure-affinity relationships (SARs) and SKRs of the reference compound MK-0483, its diastereomers, and its structural analogues as CCR2 antagonists. The SARs of the 4-arylpiperidine group suggest that lipophilic hydrogen-bond-accepting substituents at the 3-position are favorable. However, the SKRs suggest that a lipophilic group with a certain size is desired [e.g., 3-Br: Ki =2.8 nM, residence time (t(res))=243 min; 3-iPr: Ki =3.6 nM, t(res) =266 min]. Alternatively, additional substituents and further optimization of the molecule, while keeping a carboxylic acid at the 3-position, can also prolong t(res); this was most prominently observed in MK-0483 (Ki =1.2 nM, t(res) =724 min) and a close analogue (Ki =7.8 nM) with a short residence time.


Asunto(s)
Ciclopentanos/farmacología , Piperidinas/farmacología , Receptores CCR2/antagonistas & inhibidores , Animales , Ciclopentanos/síntesis química , Ciclopentanos/química , Relación Dosis-Respuesta a Droga , Cinética , Conformación Molecular , Piperidinas/síntesis química , Piperidinas/química , Relación Estructura-Actividad , Factores de Tiempo
17.
Eur J Med Chem ; 93: 121-34, 2015 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-25666912

RESUMEN

Chemokine ligand 2 (CCL2) mediates chemotaxis of monocytes to inflammatory sites via interaction with its G protein-coupled receptor CCR2. Preclinical animal models suggest that the CCL2-CCR2 axis has a critical role in the development and maintenance of inflammatory disease states (e.g., multiple sclerosis, atherosclerosis, insulin resistance, restenosis, and neuropathic pain), which can be treated through inhibition of the CCR2 receptor. However, in clinical trials high-affinity inhibitors of CCR2 have often demonstrated a lack of efficacy. We have previously described a new approach for the design of high-affinity CCR2 antagonists, by taking their residence time (RT) on the receptor into account. Here, we report our findings on both structure-affinity relationship (SAR) and structure-kinetic relationship (SKR) studies for a series of 3-((inden-1-yl)amino)-1-isopropyl-cyclopentane-1-carboxamides as CCR2 antagonists. SAR studies showed that this class of compounds tolerates a vast diversity of substituents on the indenyl ring with only small changes in affinity. However, the SKR is affected greatly by minor modifications of the structure. The combination of SAR and SKR in the hit-to-lead process resulted in the discovery of a new high-affinity and long-residence-time CCR2 antagonist (compound 15a, Ki = 2.4 nM; RT = 714 min).


Asunto(s)
Quimiocina CCL2/antagonistas & inhibidores , Ciclopentanos/síntesis química , Animales , Línea Celular Tumoral , Quimiocina CCL2/genética , Ciclopentanos/química , Ciclopentanos/farmacología , Humanos , Cinética , Estructura Molecular , Unión Proteica , Estereoisomerismo , Relación Estructura-Actividad , Factores de Tiempo , Transfección
18.
J Med Chem ; 57(8): 3382-400, 2014 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-24673104

RESUMEN

A structure-based drug design strategy was used to optimize a novel benzolactam series of HSP90α/ß inhibitors to achieve >1000-fold selectivity versus the HSP90 endoplasmic reticulum and mitochondrial isoforms (GRP94 and TRAP1, respectively). Selective HSP90α/ß inhibitors were found to be equipotent to pan-HSP90 inhibitors in promoting the clearance of mutant huntingtin protein (mHtt) in vitro, however with less cellular toxicity. Improved tolerability profiles may enable the use of HSP90α/ß selective inhibitors in treating chronic neurodegenerative indications such as Huntington's disease (HD). A potent, selective, orally available HSP90α/ß inhibitor was identified (compound 31) that crosses the blood-brain barrier. Compound 31 demonstrated proof of concept by successfully reducing brain Htt levels following oral dosing in rats.


Asunto(s)
Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Enfermedad de Huntington/tratamiento farmacológico , Animales , Diseño de Fármacos , Proteínas HSP90 de Choque Térmico/química , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
19.
J Med Chem ; 56(19): 7706-14, 2013 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-24028535

RESUMEN

Preclinical models of inflammatory diseases (e.g., neuropathic pain, rheumatoid arthritis, and multiple sclerosis) have pointed to a critical role of the chemokine receptor 2 (CCR2) and chemokine ligand 2 (CCL2). However, one of the biggest problems of high-affinity inhibitors of CCR2 is their lack of efficacy in clinical trials. We report a new approach for the design of high-affinity and long-residence-time CCR2 antagonists. We developed a new competition association assay for CCR2, which allows us to investigate the relation of the structure of the ligand and its receptor residence time [i.e., structure-kinetic relationship (SKR)] next to a traditional structure-affinity relationship (SAR). By applying combined knowledge of SAR and SKR, we were able to re-evaluate the hit-to-lead process of cyclopentylamines as CCR2 antagonists. Affinity-based optimization yielded compound 1 with good binding (Ki = 6.8 nM) but very short residence time (2.4 min). However, when the optimization was also based on residence time, the hit-to-lead process yielded compound 22a, a new high-affinity CCR2 antagonist (3.6 nM), with a residence time of 135 min.


Asunto(s)
Ciclopentanos/síntesis química , Indanos/síntesis química , Indenos/síntesis química , Receptores CCR2/antagonistas & inhibidores , Unión Competitiva , Línea Celular Tumoral , Ciclopentanos/química , Ciclopentanos/farmacología , Humanos , Indanos/química , Indanos/farmacología , Indenos/química , Indenos/farmacología , Cinética , Ligandos , Estereoisomerismo , Relación Estructura-Actividad , Tetrahidronaftalenos/síntesis química , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacología
20.
J Med Chem ; 51(17): 5243-63, 2008 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-18690678

RESUMEN

The discovery of new antibacterial agents with novel mechanisms of action is necessary to overcome the problem of bacterial resistance that affects all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV are well-characterized clinically validated targets of the fluoroquinolone antibiotics which exert their antibacterial activity through inhibition of the catalytic subunits. Inhibition of these targets through interaction with their ATP sites has been less clinically successful. The discovery and characterization of a new class of low molecular weight, synthetic inhibitors of gyrase and topoisomerase IV that bind to the ATP sites are presented. The benzimidazole ureas are dual targeting inhibitors of both enzymes and possess potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. The discovery and optimization of this novel class of antibacterials by the use of structure-guided design, modeling, and structure-activity relationships are described. Data are presented for enzyme inhibition, antibacterial activity, and in vivo efficacy by oral and intravenous administration in two rodent infection models.


Asunto(s)
Antibacterianos/química , Bencimidazoles/farmacología , Topoisomerasa de ADN IV/antagonistas & inhibidores , Inhibidores de Topoisomerasa II , Urea/análogos & derivados , Animales , Antibacterianos/farmacología , Proteínas Bacterianas , Bencimidazoles/química , Sitios de Unión , Diseño de Fármacos , Pruebas de Sensibilidad Microbiana , Roedores , Relación Estructura-Actividad , Urea/farmacología
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