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1.
Nature ; 597(7878): 698-702, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34526714

RESUMEN

The development of new antibiotics to treat infections caused by drug-resistant Gram-negative pathogens is of paramount importance as antibiotic resistance continues to increase worldwide1. Here we describe a strategy for the rational design of diazabicyclooctane inhibitors of penicillin-binding proteins from Gram-negative bacteria to overcome multiple mechanisms of resistance, including ß-lactamase enzymes, stringent response and outer membrane permeation. Diazabicyclooctane inhibitors retain activity in the presence of ß-lactamases, the primary resistance mechanism associated with ß-lactam therapy in Gram-negative bacteria2,3. Although the target spectrum of an initial lead was successfully re-engineered to gain in vivo efficacy, its ability to permeate across bacterial outer membranes was insufficient for further development. Notably, the features that enhanced target potency were found to preclude compound uptake. An improved optimization strategy leveraged porin permeation properties concomitant with biochemical potency in the lead-optimization stage. This resulted in ETX0462, which has potent in vitro and in vivo activity against Pseudomonas aeruginosa plus all other Gram-negative ESKAPE pathogens, Stenotrophomonas maltophilia and biothreat pathogens. These attributes, along with a favourable preclinical safety profile, hold promise for the successful clinical development of the first novel Gram-negative chemotype to treat life-threatening antibiotic-resistant infections in more than 25 years.


Asunto(s)
Antibacterianos/farmacología , Diseño de Fármacos , Farmacorresistencia Bacteriana Múltiple , Bacterias Gramnegativas/efectos de los fármacos , Animales , Antibacterianos/química , Compuestos Aza/química , Compuestos Aza/farmacología , Ciclooctanos/química , Ciclooctanos/farmacología , Femenino , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Proteínas de Unión a las Penicilinas/antagonistas & inhibidores , Pseudomonas aeruginosa/efectos de los fármacos , beta-Lactamasas
2.
Bioorg Med Chem ; 28(24): 115826, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33160146

RESUMEN

UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase (LpxC), the zinc metalloenzyme catalyzing the first committed step of lipid A biosynthesis in Gram-negative bacteria, has been a target for antibacterial drug discovery for many years. All inhibitor chemotypes reaching an advanced preclinical stage and clinical phase 1 have contained terminal hydroxamic acid, and none have been successfully advanced due, in part, to safety concerns, including hemodynamic effects. We hypothesized that the safety of LpxC inhibitors could be improved by replacing the terminal hydroxamic acid with a different zinc-binding group. After choosing an N-hydroxyformamide zinc-binding group, we investigated the structure-activity relationship of each part of the inhibitor scaffold with respect to Pseudomonas aeruginosa and Escherichia coli LpxC binding affinity, in vitro antibacterial potency and pharmacological properties. We identified a novel, potency-enhancing hydrophobic binding interaction for an LpxC inhibitor. We demonstrated in vivo efficacy of one compound in a neutropenic mouse E. coli infection model. Another compound was tested in a rat hemodynamic assay and was found to have a hypotensive effect. This result demonstrated that replacing the terminal hydroxamic acid with a different zinc-binding group was insufficient to avoid this previously recognized safety issue with LpxC inhibitors.


Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/farmacología , Inhibidores Enzimáticos/química , Formamidas/química , Hemodinámica/efectos de los fármacos , Amidohidrolasas/metabolismo , Animales , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/uso terapéutico , Sitios de Unión , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Escherichia coli/efectos de los fármacos , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/patología , Femenino , Formamidas/metabolismo , Formamidas/farmacología , Formamidas/uso terapéutico , Semivida , Masculino , Ratones , Simulación de Dinámica Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
3.
J Med Chem ; 63(21): 12511-12525, 2020 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-32658473

RESUMEN

Multidrug resistant Gram-negative bacterial infections are an increasing public health threat due to rapidly rising resistance toward ß-lactam antibiotics. The hydrolytic enzymes called ß-lactamases are responsible for a large proportion of the resistance phenotype. ß-Lactamase inhibitors (BLIs) can be administered in combination with ß-lactam antibiotics to negate the action of the ß-lactamases, thereby restoring activity of the ß-lactam. Newly developed BLIs offer some advantage over older BLIs in terms of enzymatic spectrum but are limited to the intravenous route of administration. Reported here is a novel, orally bioavailable diazabicyclooctane (DBO) ß-lactamase inhibitor. This new DBO, ETX1317, contains an endocyclic carbon-carbon double bond and a fluoroacetate activating group and exhibits broad spectrum activity against class A, C, and D serine ß-lactamases. The ester prodrug of ETX1317, ETX0282, is orally bioavailable and, in combination with cefpodoxime proxetil, is currently in development as an oral therapy for multidrug resistant and carbapenem-resistant Enterobacterales infections.


Asunto(s)
Antibacterianos/química , Compuestos de Azabiciclo/química , Inhibidores de beta-Lactamasas/química , beta-Lactamasas/química , Administración Oral , Animales , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Compuestos de Azabiciclo/metabolismo , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/uso terapéutico , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Semivida , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Proteínas de Unión a las Penicilinas/química , Proteínas de Unión a las Penicilinas/metabolismo , Profármacos/química , Profármacos/metabolismo , Unión Proteica , Ratas , Enfermedades de la Piel/tratamiento farmacológico , Enfermedades de la Piel/patología , Enfermedades de la Piel/veterinaria , Relación Estructura-Actividad , Inhibidores de beta-Lactamasas/metabolismo , Inhibidores de beta-Lactamasas/farmacología , Inhibidores de beta-Lactamasas/uso terapéutico , beta-Lactamasas/metabolismo
4.
J Comput Aided Mol Des ; 32(4): 573-582, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29582229

RESUMEN

Antagonism of CCR9 is a promising mechanism for treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. There is limited experimental data on CCR9 and its ligands, complicating efforts to identify new small molecule antagonists. We present here results of a successful virtual screening and rational hit-to-lead campaign that led to the discovery and initial optimization of novel CCR9 antagonists. This work uses a novel data fusion strategy to integrate the output of multiple computational tools, such as 2D similarity search, shape similarity, pharmacophore searching, and molecular docking, as well as the identification and incorporation of privileged chemokine fragments. The application of various ranking strategies, which combined consensus and parallel selection methods to achieve a balance of enrichment and novelty, resulted in 198 virtual screening hits in total, with an overall hit rate of 18%. Several hits were developed into early leads through targeted synthesis and purchase of analogs.


Asunto(s)
Simulación por Computador , Simulación del Acoplamiento Molecular/métodos , Receptores CCR/agonistas , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Ligandos , Estructura Molecular , Análisis de Componente Principal , Receptores CXCR4/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-Actividad
5.
Bioorg Med Chem Lett ; 27(8): 1670-1680, 2017 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-28302397

RESUMEN

The emergence and spread of multidrug-resistant (MDR) Gram negative bacteria presents a serious threat for public health. Novel antimicrobials that could overcome the resistance problems are urgently needed. UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) is a cytosolic zinc-based deacetylase that catalyzes the first committed step in the biosynthesis of lipid A, which is essential for the survival of Gram-negative bacteria. Our efforts toward the discovery of novel LpxC inhibitors are presented herein.


Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/química , Antibacterianos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/enzimología , Amidohidrolasas/metabolismo , Descubrimiento de Drogas , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Humanos , Simulación del Acoplamiento Molecular
6.
Bioorg Med Chem Lett ; 26(14): 3322-3325, 2016 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-27256913

RESUMEN

Irritable bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) are serious chronic diseases affecting millions of patients worldwide. Studies of human chemokine biology has suggested C-C chemokine receptor 9 (CCR9) may be a key mediator of pro-inflammatory signaling. Discovery of agents that inhibit CCR9 may lead to new therapies for CD and UC patients. Herein we describe the evolution of a high content screening hit (1) into potent inhibitors of CCR9, such as azaindole 12.


Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Descubrimiento de Drogas , Indoles/farmacología , Receptores CCR/antagonistas & inhibidores , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Indoles/síntesis química , Indoles/química , Estructura Molecular , Receptores CCR/metabolismo , Relación Estructura-Actividad
7.
J Med Chem ; 59(10): 4948-64, 2016 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-27144831

RESUMEN

In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.


Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos Organofosforados/farmacología , Fosfinas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Administración Oral , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Ratones , Ratones SCID , Conformación Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/química , Fosfinas/farmacología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad
8.
ACS Med Chem Lett ; 7(4): 374-8, 2016 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-27096044

RESUMEN

The ATPase subunit of DNA gyrase B is an attractive antibacterial target due to high conservation across bacteria and the essential role it plays in DNA replication. A novel class of pyrazolopyridone inhibitors was discovered by optimizing a fragment screening hit scaffold using structure guided design. These inhibitors show potent Gram-positive antibacterial activity and low resistance incidence against clinically important pathogens.

9.
ACS Med Chem Lett ; 6(10): 1080-5, 2015 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-26487916

RESUMEN

Antibacterials with a novel mechanism of action offer a great opportunity to combat widespread antimicrobial resistance. Bacterial DNA Gyrase is a clinically validated target. Through physiochemical property optimization of a pyrazolopyridone hit, a novel class of GyrB inhibitors were discovered. Guided by structure-based drug design, indazole derivatives with excellent enzymatic and antibacterial activity as well as great animal efficacy were discovered.

10.
J Med Chem ; 58(21): 8503-12, 2015 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-26460684

RESUMEN

The emergence and spread of multidrug resistant bacteria are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors and detail the story of their evolution from a de novo design hit based on structure-based drug design. These inhibitors show potent minimum inhibitory concentrations against fluoroquinolone resistant MRSA and other Gram-positive bacteria.


Asunto(s)
Proteínas Bacterianas/antagonistas & inhibidores , Girasa de ADN/metabolismo , Indoles/farmacología , Staphylococcus aureus Resistente a Meticilina/enzimología , Inhibidores de Topoisomerasa II/farmacología , Urea/farmacología , Proteínas Bacterianas/metabolismo , Cristalografía por Rayos X , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/enzimología , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Indoles/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Modelos Moleculares , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Inhibidores de Topoisomerasa II/química , Urea/análogos & derivados
11.
Bioorg Med Chem Lett ; 25(17): 3661-4, 2015 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-26117562

RESUMEN

Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, affects millions of people worldwide. CCR9 has been shown to be a key chemokine receptor mediating the local inflammatory responses in the GI tract. The CCR9 inhibitor Vercirnon advanced to phase 3 clinical trials, but carries several liabilities which we sought to improve.


Asunto(s)
Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Receptores CCR/antagonistas & inhibidores , Sulfonamidas/química , Sulfonamidas/farmacología , Animales , Técnicas de Química Sintética , Evaluación Preclínica de Medicamentos/métodos , Humanos , Concentración 50 Inhibidora , Ratones , Relación Estructura-Actividad
12.
Bioorg Med Chem Lett ; 21(12): 3743-8, 2011 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-21561767

RESUMEN

Ponatinib (AP24534) was previously identified as a pan-BCR-ABL inhibitor that potently inhibits the T315I gatekeeper mutant, and has advanced into clinical development for the treatment of refractory or resistant CML. In this study, we explored a novel series of five and six membered monocycles as alternate hinge-binding templates to replace the 6,5-fused imidazopyridazine core of ponatinib. Like ponatinib, these monocycles are tethered to pendant toluanilides via an ethynyl linker. Several compounds in this series displayed excellent in vitro potency against both native BCR-ABL and the T315I mutant. Notably, a subset of inhibitors exhibited desirable PK and were orally active in a mouse model of T315I-driven CML.


Asunto(s)
Alquinos/síntesis química , Alquinos/farmacología , Compuestos de Anilina/síntesis química , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Tolueno/síntesis química , Administración Oral , Alquinos/química , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Ciclización , Modelos Animales de Enfermedad , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Ratones , Modelos Moleculares , Estructura Molecular , Mutación , Ratas , Relación Estructura-Actividad , Tolueno/química , Tolueno/farmacología
13.
J Med Chem ; 53(12): 4701-19, 2010 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-20513156

RESUMEN

In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of Ile315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC(50)s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL(T315I) expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CML, including patients refractory to all currently approved therapies.


Asunto(s)
Antineoplásicos/síntesis química , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Imidazoles/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Piridazinas/síntesis química , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Barrera Hematoencefálica/metabolismo , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Proteínas de Fusión bcr-abl/genética , Imidazoles/farmacocinética , Imidazoles/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Ratones , Ratones SCID , Modelos Moleculares , Mutación , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Piridazinas/farmacocinética , Piridazinas/farmacología , Ratas
15.
J Am Chem Soc ; 125(50): 15521-8, 2003 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-14664599

RESUMEN

Lewis acid-mediated nucleophilic substitution reactions of substituted tetrahydropyran acetates reveal that the conformational preferences of six-membered-ring cations depend significantly upon the electronic nature of the substituent. Nucleophilic substitutions of C-3 and C-4 alkyl-substituted tetrahydropyran acetates proceeded via pseudoequatorially substituted oxocarbenium ions, as would be expected by consideration of steric effects. Substitutions of C-3 and C-4 alkoxy-substituted tetrahydropyran acetates, however, proceeded via pseudoaxially oriented oxocarbenium ions. The unusual selectivities controlled by the alkoxy groups were demonstrated for a range of other heteroatom substituents, including nitrogen, fluorine, chlorine, and bromine. It is believed that the pseudoaxial conformation is preferred in the ground state of the cation because of an electrostatic attraction between the cationic carbon center of the oxocarbenium ion and the heteroatom substituent. This analysis is supported by the observation that selectivity diminishes down the halogen series, which is inconsistent with electron donation as might be expected during anchimeric assistance. The C-2 heteroatom-substituted systems gave moderately high 1,2-cis selectivity, while small alkyl substituents showed no selectivity. Only in the case of the tert-butyl group at C-2 was high 1,2-trans selectivity observed. These studies reinforce the idea that ground-state conformational effects need to be considered along with steric approach considerations.


Asunto(s)
Piranos/química , Cationes , Conformación Molecular , Electricidad Estática , Estereoisomerismo
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