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1.
Bioorg Med Chem Lett ; 28(23-24): 3766-3773, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30340896

RESUMO

Endogenous nitrosothiols (SNOs) including S-nitrosoglutathione (GSNO) serve as reservoir for bioavailable nitric oxide (NO) and mediate NO-based signaling, inflammatory status and smooth muscle function in the lung. GSNOR inhibition increases pulmonary GSNO and induces bronchodilation while reducing inflammation in lung diseases. In this letter, design, synthesis and structure-activity relationships (SAR) of novel imidazole-biaryl-tetrazole based GSNOR inhibitors are described. Many potent inhibitors (30, 39, 41, 42, 44, 45 and 58) were identified with low nanomolar activity (IC50s: <15 nM) along with adequate metabolic stability. Lead compounds 30 and 58 exhibited good exposure and oral bioavailability in mouse pharmacokinetic (PK) study. Compound 30 was selected for further profiling and revealed comparable mouse and rat GSNOR potency, high selectivity against alcohol dehydrogenase (ADH) and carbonyl reductase (CBR1) family of enzymes, low efflux ratio and permeability in PAMPA, a high permeability in CALU-3 assay, significantly low hERG activity and minimal off-target activity. Further, an in vivo efficacy of compound 30 is disclosed in cigarette smoke (CS) induced mouse model for COPD.


Assuntos
Aldeído Oxirredutases/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tetrazóis/química , Tetrazóis/farmacologia , Administração Oral , Aldeído Oxirredutases/metabolismo , Animais , Fumar Cigarros/efeitos adversos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Halogenação , Humanos , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Relação Estrutura-Atividade , Tetrazóis/administração & dosagem , Tetrazóis/farmacocinética
2.
Bioorg Med Chem Lett ; 28(7): 1211-1218, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29519738

RESUMO

In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160-950 nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases. Most of the tested analogs demonstrated required metabolic stability in liver microsomes, low hERG and CYP liability. Oral pharmacokinetics and bioavailability of lead compounds 21j, 21m and 21p are discussed in multiple species like rat, guinea pig, dog, and cynomolgus monkey. Besides, these compounds revealed low to moderate activity against human pregnane X receptor (hPXR). The selected lead 21j further demonstrated in vivo efficacy in acute hyperalgesia (ED50: 39.6 mg/kg) and MIA-induced osteoarthritic pain models (ED50: 106 mg/kg).


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores Enzimáticos/farmacologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Furanos/farmacologia , Imidazóis/farmacologia , Prostaglandina-E Sintases/antagonistas & inibidores , Administração Oral , Animais , Linhagem Celular Tumoral , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Furanos/administração & dosagem , Furanos/química , Cobaias , Humanos , Hiperalgesia/tratamento farmacológico , Imidazóis/administração & dosagem , Imidazóis/química , Macaca fascicularis , Estrutura Molecular , Dor/tratamento farmacológico , Prostaglandina-E Sintases/metabolismo , Ratos , Relação Estrutura-Atividade
3.
Arch Pharm (Weinheim) ; 351(2)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29292534

RESUMO

Design, synthesis, and biological screening of 2,2-dimethyl-2,3-dihydrobenzofuran tethered 1,3,4-oxadiazole derivatives as anti-tubercular agents were described. The synthesis of the target compounds was conducted by a series of reaction schemes. All the synthesized compounds were characterized by IR, 1 H NMR, 13 C NMR, and mass spectrometry. The therapeutic potential of the synthesized compounds was confirmed by molecular docking studies. Among the synthesized compounds, 12a, 12c, 12d, 12e, 12g, and 12j were found to be more active against non-replicating than against replicating cultures of Mycobacterium tuberculosis H37Ra ex vivo and in vitro. These compounds exhibit minimum inhibitory concentration (MIC) values in the range of 2.31-23.91 µg/mL. The cytotoxicity study was conducted against the cell lines THP-1, A549 and PANC-1, and the compounds were observed to be non-toxic to host cells. Molecular docking was conducted with InhA (FabI/ENR) and suggested the antimycobacterial potential of the synthesized compounds. The investigation presented here was found to be adventitious for the development of new therapeutic agents against Mycobacterium infection.


Assuntos
Antituberculosos/farmacologia , Azóis/farmacologia , Desenho de Fármacos , Infecções por Mycobacterium/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/síntese química , Antituberculosos/química , Azóis/síntese química , Azóis/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Halogenação , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 27(23): 5131-5138, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29100801

RESUMO

This letter describes the synthesis and biological evaluation of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as novel mPGES-1 inhibitors, capable of inhibiting an increased PGE2 production in the disease state. Structure-activity optimization afforded many potent mPGES-1 inhibitors having <50 nM potencies in the A549 cellular assay and adequate metabolic stability in liver microsomes. Lead compounds 8l and 8m demonstrated reasonable in vitro pharmacology and pharmacokinetic properties over other compounds. In particular, 8m revealed satisfactory oral pharmacokinetics and bioavailability in multiple species like rat, guinea pig, dog and cynomolgus monkey. In addition, the representative compound 8m showed in vivo efficacy by inhibiting LPS-induced thermal hyperalgesia with an ED50 of 14.3 mg/kg in guinea pig.


Assuntos
Inibidores Enzimáticos/química , Furanos/química , Imidazóis/química , Prostaglandina-E Sintases/antagonistas & inibidores , Células A549 , Administração Oral , Animais , Cães , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Cobaias , Meia-Vida , Humanos , Hiperalgesia/tratamento farmacológico , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Concentração Inibidora 50 , Macaca fascicularis , Microssomos Hepáticos/metabolismo , Prostaglandina-E Sintases/metabolismo , Ratos , Solubilidade , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 27(11): 2594-2601, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28400234

RESUMO

A series of substituted tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives have been synthesized and their mPGES-1 biological activity has been disclosed in detail. Structure-activity relationship (SAR) optimization provided inhibitors with excellent mPGES-1 potency and low to moderate PGE2 release A549 cell potency. Among the mPGES-1 inhibitors studied, 7, 9 and 11l provided excellent selectivity over COX-2 (>200-fold) and >70-fold selectivity for COX-1 except 11l, which exhibited dual mPGES-1/COX-1 activity. Furthermore, the above tested mPGES-1 inhibitors demonstrated good metabolic stability in liver microsomes, high plasma protein binding (PPB) and no significant inhibition observed in clinically relevant CYP isoforms. Besides, selected mPGES-1 tool compounds 9 and 11l provided good in vivo pharmacokinetic profile and oral bioavailability (%F=33 and 85). Additionally, the representative mPGES-1 tool compounds 9 and 11l revealed moderate in vivo efficacy in the LPS-induced thermal hyperalgesia guinea pig pain model.


Assuntos
Imidazóis/química , Prostaglandina-E Sintases/antagonistas & inibidores , Células A549 , Administração Oral , Animais , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Cobaias , Meia-Vida , Humanos , Hiperalgesia/tratamento farmacológico , Imidazóis/síntese química , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Concentração Inibidora 50 , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Prostaglandina-E Sintases/genética , Prostaglandina-E Sintases/metabolismo , Ratos , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 26(24): 5977-5984, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27865703

RESUMO

The discovery and SAR of potent, selective dioxane-fused tricyclic benz[d]imidazole derivatives as mPGES-1 inhibitor are herein described. Various amide modifications in this series afforded many potent mPGES-1 inhibitors, of which 17d proved to be suitable for further profiling in vivo. Compound 17d {2-((2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino[2',3':3,4]benzo[1,2-d]imidazole-5-carboxamide} exhibited excellent mPGES-1 enzyme (IC50: 8nM), cell (A549 IC50: 16.24nM) and human whole blood potency (IC50: 249.9nM). In rodent species, 17d strongly inhibited guinea pig mPGES-1 (IC50: 10.79nM), but not the rat and mouse enzyme. Furthermore 17d displayed excellent in vitro selectivity over mPGES-2, cPGES, COX-enzymes (COX-1, 2), selectivity against other prostanoid synthases, favorable hERG and CEREP panel profile. Likewise, our lead 17d demonstrated good oral pharmacokinetic profiles and good CNS B/P ratio in rat and guinea pig. Lead 17d also unveiled good efficacy in LPS-induced thermal hyperalgesia pain model with ED50 of 36.7mg/kg, respectively.


Assuntos
Benzimidazóis/farmacologia , Dioxanos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hiperalgesia/tratamento farmacológico , Dor/tratamento farmacológico , Prostaglandina-E Sintases/antagonistas & inibidores , Animais , Benzimidazóis/síntese química , Benzimidazóis/química , Dioxanos/síntese química , Dioxanos/química , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Cobaias , Temperatura Alta , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Prostaglandina-E Sintases/metabolismo , Ratos , Relação Estrutura-Atividade
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