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1.
ACS Med Chem Lett ; 14(6): 853-859, 2023 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-37312855

RESUMO

Herein we report the development of an automated deoxygenative C(sp2)-C(sp3) coupling of aryl bromide with alcohols to enable parallel medicinal chemistry. Alcohols are among the most diverse and abundant building blocks, but their usage as alkyl precursors has been limited. Although metallaphotoredox deoxygenative coupling is becoming a promising strategy to form C(sp2)-C(sp3) bond, the reaction setup limits its widespread application in library synthesis. To achieve high throughput and consistency, an automated workflow involving solid-dosing and liquid-handling robots has been developed. We have successfully demonstrated this high-throughput protocol is robust and consistent across three automation platforms. Furthermore, guided by cheminformatic analysis, we examined alcohols with comprehensive chemical space coverage and established a meaningful scope for medicinal chemistry applications. By accessing the rich diversity of alcohols, this automated protocol has the potential to substantially increase the impact of C(sp2)-C(sp3) cross-coupling in drug discovery.

2.
J Med Chem ; 61(14): 6236-6246, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-29965759

RESUMO

A novel series of 2,4-diaminoquinazolines was identified as potent dual Toll-like receptor (TLR) 7 and 8 agonists with reduced off-target activity. The stereochemistry of the amino alcohol was found to influence the TLR7/8 selectivity with the ( R) isomer resulting in selective TLR8 agonism. Lead optimization toward a dual agonist afforded ( S)-3-((2-amino-8-fluoroquinazolin-4-yl)amino)hexanol 31 as a potent analog, being structurally different from previously described dual agonists ( McGowan J. Med. Chem. 2016 , 59 , 7936 ). Pharmacokinetic and pharmacodynamic (PK/PD) studies revealed the desired high first pass profile aimed at limiting systemic cytokine activation. In vivo pharmacodynamic studies with lead compound 31 demonstrated production of cytokines consistent with TLR7/8 activation in mice and cynomolgus monkeys and ex vivo inhibition of hepatitis B virus (HBV).


Assuntos
Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Quinazolinas/farmacologia , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismo , Animais , Antivirais/química , Antivirais/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Conformação Proteica , Quinazolinas/química , Quinazolinas/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Receptor 7 Toll-Like/química , Receptor 8 Toll-Like/química
3.
Bioorg Med Chem Lett ; 28(4): 711-719, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29366653

RESUMO

The discovery of a novel series of highly potent quinazoline TLR 7/8 agonists is described. The synthesis and structure-activity relationship is presented. Structural requirements and optimization of this series toward TLR 7 selectivity afforded the potent agonist 48. Pharmacokinetic and pharmacodynamic studies highlighted 48 as an orally available endogenous interferon (IFN-α) inducer in mice.


Assuntos
Glicoproteínas de Membrana/agonistas , Quinazolinas/farmacologia , Receptor 7 Toll-Like/agonistas , Animais , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Inibidores das Enzimas do Citocromo P-450/farmacologia , Células HEK293 , Meia-Vida , Humanos , Interferon-alfa/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/farmacocinética , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Receptor 8 Toll-Like/agonistas
4.
Antiviral Res ; 147: 149-158, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29037976

RESUMO

Dengue is the most important mosquito-transmitted viral disease and a major global health concern. Over the last decade, dengue virus (DENV) drug discovery and development has intensified, however, this has not resulted in approved DENV-specific antiviral treatments yet. DENV and hepatitis C virus (HCV) belong to the same Flaviviridae family and, in contrast to DENV, antiviral treatments for HCV have been licensed. Therefore, applying the knowledge gained on anti-HCV drugs may foster the discovery and development of dengue antiviral drugs. Here, we screened a library of compounds with established anti-HCV activity in a DENV-2 sub-genomic replicon inhibition assay and selected compounds with single-digit micromolar activity. These compounds were advanced into a hit-to-lead medicinal chemistry program resulting in lead compound JNJ-1A, which inhibited the DENV-2 sub-genomic replicon at 0.7 µM, in the absence of cytotoxicity. In addition, JNJ-1A showed equipotent antiviral activity against DENV serotypes 1, 2, and 4. In vitro resistance selection experiments with JNJ-1A induced mutation T108I in non-structural protein 4B (NS4B), pointing towards a mechanism of action linked to this protein. Collectively, we described the discovery and characterization of a novel DENV inhibitor potentially targeting NS4B.


Assuntos
Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Farmacorresistência Viral/genética , Proteínas não Estruturais Virais/genética , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacocinética , Antivirais/toxicidade , Linhagem Celular Tumoral , Chlorocebus aethiops , Dengue , Vírus da Dengue/genética , Vírus da Dengue/fisiologia , Descoberta de Drogas , Farmacorresistência Viral/efeitos dos fármacos , Hepacivirus/genética , Humanos , Mutação , RNA Viral/genética , Replicon/efeitos dos fármacos , Análise de Sequência de RNA , Bibliotecas de Moléculas Pequenas , Células Vero
5.
J Med Chem ; 60(14): 6137-6151, 2017 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-28671847

RESUMO

Pyrrolo[3,2-d]pyrimidines were identified as a new series of potent and selective TLR7 agonists. Compounds were optimized for their activity and selectivity over TLR8. This presents an advantage over recently described scaffolds that have residual TLR8 activity, which may be detrimental to the tolerability of the candidate drug. Oral administration of the lead compound 54 effectively induced a transient interferon stimulated gene (ISG) response in mice and cynomolgus monkeys. We aimed for a high first pass effect, limiting cytokine induction systemically, and demonstrated the potential for the immunotherapy of viral hepatitis.


Assuntos
Antivirais/síntese química , Hepatite B/tratamento farmacológico , Pirimidinas/síntese química , Pirróis/síntese química , Receptor 7 Toll-Like/agonistas , Administração Oral , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Cães , Feminino , Genes Reporter , Células HEK293 , Hepatite B/imunologia , Humanos , Imunoterapia , Interferons/biossíntese , Macaca fascicularis , Células Madin Darby de Rim Canino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Relação Estrutura-Atividade , Receptor 7 Toll-Like/genética , Receptor 8 Toll-Like/agonistas , Receptor 8 Toll-Like/genética
6.
J Med Chem ; 59(17): 7936-49, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27513093

RESUMO

Toll-like receptor (TLR) 7 and 8 agonists can potentially be used in the treatment of viral infections and are particularly promising for chronic hepatitis B virus (HBV) infection. An internal screening effort identified a pyrimidine Toll-like receptor 7 and 8 dual agonist. This provided a novel alternative over the previously reported adenine and pteridone type of agonists. Structure-activity relationship, lead optimization, in silico docking, pharmacokinetics, and demonstration of ex vivo and in vivo cytokine production of the lead compound are presented.


Assuntos
Antivirais/química , Vírus da Hepatite B/efeitos dos fármacos , Pirimidinas/química , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Antivirais/farmacologia , Simulação por Computador , Citocinas/biossíntese , Cães , Hepatite B/tratamento farmacológico , Hepatite B/virologia , Vírus da Hepatite B/fisiologia , Ensaios de Triagem em Larga Escala , Humanos , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
7.
J Med Chem ; 57(5): 1880-92, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24144360

RESUMO

Structure-based macrocyclization of a 6-carboxylic acid indole chemotype has yielded potent and selective finger-loop inhibitors of the hepatitis C virus (HCV) NS5B polymerase. Lead optimization in conjunction with in vivo evaluation in rats identified several compounds showing (i) nanomolar potency in HCV replicon cells, (ii) limited toxicity and off-target activities, and (iii) encouraging preclinical pharmacokinetic profiles characterized by high liver distribution. This effort culminated in the identification of TMC647055 (10a), a nonzwitterionic 17-membered-ring macrocycle characterized by high affinity, long polymerase residence time, and broad genotypic coverage. In vitro results of the combination of 10a with the HCV protease inhibitor TMC435 (simeprevir) supported an evaluation of this combination in patients with regard to virus suppression and resistance emergence. In a phase 1b trial with HCV genotype 1-infected patients, 10a was considered to be safe and well-tolerated and demonstrated potent antiviral activity, which was further enhanced in a combination study with TMC435.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Cristalografia por Raios X , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética
8.
Bioorg Med Chem Lett ; 22(13): 4437-43, 2012 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-22633687

RESUMO

Optimization of a novel series of macrocyclic indole-based inhibitors of the HCV NS5b polymerase targeting the finger loop domain led to the discovery of lead compounds exhibiting improved potency in cellular assays and superior pharmacokinetic profile. Further lead optimization performed on the most promising unsaturated-bridged subseries provided the clinical candidate 27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1H,11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H,15H)-dione, TMC647055 (compound 18a). This non-zwitterionic 17-membered ring macrocycle combines nanomolar cellular potency (EC(50) of 82 nM) with minimal associated cell toxicity (CC(50)>20 µM) and promising pharmacokinetic profiles in rats and dogs. TMC647055 is currently being evaluated in the clinic.


Assuntos
Antivirais/química , Inibidores Enzimáticos/química , Hepacivirus/enzimologia , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Indóis/química , Sulfonamidas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Humanos , Fígado/metabolismo , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
9.
Bioorg Med Chem Lett ; 22(13): 4431-6, 2012 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-22542193

RESUMO

Novel conformationaly constrained 1,6- and 2,6-macrocyclic HCV NS5b polymerase inhibitors, in which either the nitrogen or the phenyl ring in the C2 position of the central indole core is tethered to an acylsulfamide acid bioisostere, have been designed and tested for their anti-HCV potency. This transformational route toward non-zwitterionic finger loop-directed inhibitors led to the discovery of derivatives with improved cell potency and pharmacokinetic profile.


Assuntos
Antivirais/química , Inibidores Enzimáticos/química , Hepacivirus/enzimologia , Indóis/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Indóis/síntese química , Indóis/farmacocinética , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
11.
J Med Chem ; 52(14): 4099-102, 2009 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-19507864

RESUMO

HCV NS5B polymerase, an essential and virus-specific enzyme, is an important target for drug discovery. Using structure-based design, we optimized a 1,5-benzodiazepine NS5B polymerase inhibitor chemotype into a new sulfone-containing scaffold. The design yielded potent inhibitor (S)-4c (K(D) = 0.79 nM), which has approximately 20-fold greater affinity for NS5B than its carbonyl analogue (R)-2c.


Assuntos
Benzodiazepinas/química , Benzodiazepinas/farmacologia , Desenho de Fármacos , Hepacivirus/enzimologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Modelos Moleculares , Conformação Molecular , RNA Polimerase Dependente de RNA/química , RNA Polimerase Dependente de RNA/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
12.
Bioorg Med Chem Lett ; 19(9): 2492-6, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19342234

RESUMO

Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent (replicon EC(50)=400nM and 270nM, respectively) and selective (CC(50)>20muM) inhibitors of HCV replication. These data warrant further lead-optimization efforts.


Assuntos
Antivirais/síntese química , Benzodiazepinas/química , Química Farmacêutica/métodos , Hepacivirus/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Acrilatos/química , Antivirais/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Hepacivirus/enzimologia , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Relação Estrutura-Atividade
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