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1.
Nature ; 597(7878): 698-702, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34526714

RESUMO

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.


Assuntos
Antibacterianos/farmacologia , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas/efeitos dos fármacos , Animais , Antibacterianos/química , Compostos Aza/química , Compostos Aza/farmacologia , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Proteínas de Ligação às Penicilinas/antagonistas & inibidores , Pseudomonas aeruginosa/efeitos dos fármacos , beta-Lactamases
2.
Bioorg Med Chem ; 28(24): 115826, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33160146

RESUMO

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.


Assuntos
Amidoidrolases/antagonistas & inibidores , Antibacterianos/farmacologia , Inibidores Enzimáticos/química , Formamidas/química , Hemodinâmica/efeitos dos fármacos , Amidoidrolases/metabolismo , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/uso terapêutico , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/patologia , Feminino , Formamidas/metabolismo , Formamidas/farmacologia , Formamidas/uso terapêutico , Meia-Vida , Masculino , Camundongos , Simulação de Dinâmica Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
3.
J Comput Aided Mol Des ; 32(4): 573-582, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29582229

RESUMO

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.


Assuntos
Simulação por Computador , Simulação de Acoplamento Molecular/métodos , Receptores CCR/agonistas , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Ligantes , Estrutura Molecular , Análise de Componente Principal , Receptores CXCR4/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 27(8): 1670-1680, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28302397

RESUMO

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.


Assuntos
Amidoidrolases/antagonistas & inibidores , Antibacterianos/química , Antibacterianos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/enzimologia , Amidoidrolases/metabolismo , Descoberta de Drogas , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular
5.
Bioorg Med Chem Lett ; 26(14): 3322-3325, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27256913

RESUMO

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.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Descoberta de Drogas , Indóis/farmacologia , Receptores CCR/antagonistas & inibidores , Colite Ulcerativa/metabolismo , Doença de Crohn/metabolismo , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , Receptores CCR/metabolismo , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 25(17): 3661-4, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26117562

RESUMO

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.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Receptores CCR/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Concentração Inibidora 50 , Camundongos , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 21(12): 3743-8, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21561767

RESUMO

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.


Assuntos
Alcinos/síntese química , Alcinos/farmacologia , Compostos de Anilina/síntese química , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Tolueno/síntese química , Administração Oral , Alcinos/química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Ciclização , Modelos Animais de Doenças , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Camundongos , Modelos Moleculares , Estrutura Molecular , Mutação , Ratos , Relação Estrutura-Atividade , Tolueno/química , Tolueno/farmacologia
8.
J Med Chem ; 63(21): 12511-12525, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-32658473

RESUMO

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.


Assuntos
Antibacterianos/química , Compostos Azabicíclicos/química , Inibidores de beta-Lactamases/química , beta-Lactamases/química , Administração Oral , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/metabolismo , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Meia-Vida , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Proteínas de Ligação às Penicilinas/química , Proteínas de Ligação às Penicilinas/metabolismo , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Ligação Proteica , Ratos , Dermatopatias/tratamento farmacológico , Dermatopatias/patologia , Dermatopatias/veterinária , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/metabolismo , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico , beta-Lactamases/metabolismo
9.
ACS Med Chem Lett ; 7(4): 374-8, 2016 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-27096044

RESUMO

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.

10.
J Med Chem ; 59(10): 4948-64, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27144831

RESUMO

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.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Neoplasias Pulmonares/tratamento farmacológico , Compostos Organofosforados/farmacologia , Fosfinas/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Administração Oral , Quinase do Linfoma Anaplásico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos SCID , Conformação Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/química , Fosfinas/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade
11.
ACS Med Chem Lett ; 6(10): 1080-5, 2015 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-26487916

RESUMO

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.

12.
J Med Chem ; 58(21): 8503-12, 2015 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-26460684

RESUMO

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.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , DNA Girase/metabolismo , Indóis/farmacologia , Staphylococcus aureus Resistente à Meticilina/enzimologia , Inibidores da Topoisomerase II/farmacologia , Ureia/farmacologia , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/enzimologia , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Indóis/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Modelos Moleculares , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Inibidores da Topoisomerase II/química , Ureia/análogos & derivados
14.
J Med Chem ; 53(12): 4701-19, 2010 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-20513156

RESUMO

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.


Assuntos
Antineoplásicos/síntese química , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Imidazóis/síntese química , Inibidores de Proteínas Quinases/síntese química , Piridazinas/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Fusão bcr-abl/genética , Imidazóis/farmacocinética , Imidazóis/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Camundongos , Camundongos SCID , Modelos Moleculares , Mutação , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/farmacocinética , Piridazinas/farmacologia , Ratos
15.
J Am Chem Soc ; 125(50): 15521-8, 2003 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-14664599

RESUMO

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.


Assuntos
Piranos/química , Cátions , Conformação Molecular , Eletricidade Estática , Estereoisomerismo
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