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1.
J Med Chem ; 63(23): 15050-15071, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33261314

RESUMO

Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.

2.
Bioorg Med Chem Lett ; 30(19): 127441, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32736080

RESUMO

In an effort to discover oral inverse agonists of RORγt to treat inflammatory diseases, a new 2,6-difluorobenzyl ether series of cyclopentyl sulfones were found to be surprisingly more potent than the corresponding alcohol derivatives. When combined with a more optimized phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone template, the 2,6-difluorobenzyl ethers yielded a set of very potent RORγt inverse agonists (e.g., compound 26, RORγt Gal4 EC50 11 nM) that are highly selective against PXR, LXRα and LXRß. After optimizing for stability in human and mouse liver microsomes, compounds 29 and 38 were evaluated in vivo and found to have good oral bioavailability (56% and 101%, respectively) in mice. X-ray co-crystal structure of compound 27 in RORγt revealed that the bulky benzyl ether group causes helix 11 of the protein to partially uncoil to create a new, enlarged binding site, which nicely accommodates the benzyl ether moiety, leading to net potency gain.

3.
Bioorg Med Chem Lett ; 30(12): 127204, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32334911

RESUMO

Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.

4.
Bioorg Med Chem Lett ; 29(16): 2265-2269, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31257087

RESUMO

An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.


Assuntos
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Pirrolidinas/farmacologia , Sulfonas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Agonismo Inverso de Drogas , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/administração & dosagem , Pirrolidinas/química , Relação Estrutura-Atividade , Sulfonas/administração & dosagem , Sulfonas/química
5.
ACS Med Chem Lett ; 10(3): 367-373, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891142

RESUMO

A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of RORγt inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide 1. Through a combination of structure-based design and structure-activity relationship studies, a polar set of amides at N1-position of the pyrrolidine ring and perfluoroisopropyl group at para-position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXRα, and LXRß. Further optimization led to the discovery of (1R,4r)-4-((R)-3-((4-fluorophenyl)sulfonyl)-3-(4-(perfluoropropan-2-yl)phenyl)pyrrolidine-1-carbonyl)cyclohexane-1-carboxylic acid (26), which displayed excellent selectivity, desirable liability and pharmacokinetic properties in vitro, and a good pharmacokinetic profile in mouse. Oral administration of 26 demonstrated dose-dependent inhibition of IL-17 production in a mouse IL-2/IL-23-induced pharmacodynamic model and biologic-like efficacy in an IL-23-induced mouse acanthosis model.

6.
Bioorg Med Chem Lett ; 28(2): 85-93, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29233651

RESUMO

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Desenho de Fármacos , Propanóis/farmacologia , Receptores do Ácido Retinoico/agonistas , Receptores de Esteroides/agonistas , Sulfonamidas/farmacologia , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Receptores X do Fígado/agonistas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Receptor de Pregnano X , Propanóis/síntese química , Propanóis/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
8.
Bioorg Med Chem Lett ; 27(14): 3101-3106, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28539220

RESUMO

A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.


Assuntos
Janus Quinase 1/antagonistas & inibidores , Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Piridazinas/química , Pirróis/química , Animais , Sítios de Ligação , Domínio Catalítico , Linhagem Celular , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Inflamação/prevenção & controle , Concentração Inibidora 50 , Janus Quinase 1/metabolismo , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Janus Quinase 3/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Conformação Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Piridazinas/síntese química , Piridazinas/farmacocinética , Pirróis/síntese química , Pirróis/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , TYK2 Quinase/antagonistas & inibidores , TYK2 Quinase/metabolismo
9.
Bioorg Med Chem Lett ; 24(24): 5721-5726, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25453808

RESUMO

A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.


Assuntos
Descoberta de Drogas , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/química , Pirróis/química , Administração Oral , Animais , Ensaio de Imunoadsorção Enzimática , Humanos , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Conformação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade , Distribuição Tecidual
10.
Zhongguo Yi Liao Qi Xie Za Zhi ; 34(2): 89-91, 93, 2010 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-20540287

RESUMO

PURPOSE: Discuss the new method of individual internal fixation with steel plate customization. METHOD: Customize individual internal fixation with steel plate according to 3D reconstruction of CT images and Ugnx. Pro/E machining method. RESULT: Success in customization about the first individual internal fixation with clavicular hook plate for the treatment of multisegmental fracture of clavicle. CONCLUSION: The new method of individual internal fixation with steel plate customization according to 3D reconstruction of CT images and Ugnx, Pro/E machining technique is a good news for patients of orthopaedic trauma. We are fully confident of the future development of the method of individual internal fixation with steel plate customization.


Assuntos
Placas Ósseas , Fixação Interna de Fraturas/instrumentação , Fraturas Ósseas/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Tomografia Computadorizada Espiral/métodos , Desenho de Equipamento , Humanos , Imageamento Tridimensional , Fixadores Internos , Aço
11.
Bioorg Med Chem Lett ; 18(6): 1958-62, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18282708

RESUMO

Potent and selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered with several new heterocyclic P1' groups in conjunction with cyclic beta-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best overall profile when combined with tetrahydropyran beta-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed IC(50) value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-alpha of human whole blood. Compound 49 also displayed excellent selectivity over a wide panel of MMPs as well as excellent oral bioavailability (F%>90%) in rat n-in-1 PK studies.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Benzofuranos/química , Imidazóis/química , Indóis/química , Inibidores de Proteases/farmacologia , Pirazóis/química , Piridinas/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Ácidos Hidroxâmicos/química , Lipopolissacarídeos/farmacologia , Inibidores de Metaloproteinases de Matriz , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo
12.
Bioorg Med Chem Lett ; 18(5): 1577-82, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-18242982

RESUMO

Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1' substituents in conjunction with unique constrained beta-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-alpha Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-alpha in human whole blood and orally bioavailable.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Benzamidas/química , Benzamidas/farmacologia , Proteína ADAM17 , Animais , Área Sob a Curva , Benzamidas/sangue , Benzamidas/farmacocinética , Disponibilidade Biológica , Cães , Meia-Vida , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 18(2): 694-9, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18061445

RESUMO

Selective inhibitors of TNF-alpha Converting Enzyme (TACE) based on (1R,2S)-cyclopentyl, (3S,4S)-pyrrolidinyl, and (3R,4S)-tetrahydrofuranyl beta-benzamido hydroxamic acids have been synthesized and evaluated. This study has led to the discovery of novel inhibitors whose profiles include activity against TACE in an enzyme assay, potency in the suppression of LPS-stimulated TNF-alpha in human whole blood, selectivity against a panel of MMPs and oral bioavailability.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Proteína ADAM17 , Administração Oral , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/síntese química , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacocinética , Ratos , Estereoisomerismo
15.
Bioorg Med Chem Lett ; 17(1): 266-71, 2007 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-17027261

RESUMO

Using a pyrimidine-2,4,6-trione motif as a zinc-binding group, a series of selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) was discovered. Optimization of initial lead 1 resulted in a potent inhibitor (51), with an IC(50) of 2 nM in a porcine TACE assay. To the best of our knowledge, compound 51 and related analogues represent first examples of non-hydroxamate-based inhibitors of TACE with single digit nanomolar potency.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Barbitúricos/química , Barbitúricos/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteína ADAM17 , Barbitúricos/síntese química , Benzamidas/síntese química , Ácidos Hidroxâmicos/química , Concentração Inibidora 50 , Inibidores de Proteases/síntese química
16.
Bioorg Med Chem Lett ; 15(12): 2970-3, 2005 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-15908214

RESUMO

New inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered with a pyrimidine-2,4,6-trione in place of the commonly used hydroxamic acid. These non-hydroxamate TACE inhibitors were developed by incorporating a 4-(2-methyl-4-quinolinylmethoxy)phenyl group, an optimized TACE selective P1' group. Several leads were identified with IC50 values around 100 nM in a porcine TACE assay and selective over MMP-1, -2, -9, -13, and aggrecanase.


Assuntos
Ácidos Hidroxâmicos/química , Inibidores de Metaloproteinases de Matriz , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Pirimidinas/farmacologia , Proteínas ADAM , Proteína ADAM17 , Animais , Endopeptidases/química , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Suínos
17.
Bioorg Med Chem Lett ; 13(12): 2035-40, 2003 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-12781190

RESUMO

New inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered using an N-hydroxy-2-(2-oxo-3-pyrrolidinyl)acetamide scaffold. The series was found to be potent in a porcine TACE (pTACE) assay with IC(50)s typically below 5 nM. For most compounds, selectivity for pTACE relative to MMP-1,-2, and -9 is at least 300-fold. Compound 2o was potent in inhibition of TNFalpha production in a human whole blood assay (WBA) with an IC(50) of 0.42 micro M.


Assuntos
Acetamidas/química , Acetamidas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Metaloendopeptidases/antagonistas & inibidores , Proteínas ADAM , Proteína ADAM17 , Acetamidas/síntese química , Animais , Humanos , Concentração Inibidora 50 , Lactamas/química , Lactamas/farmacologia , Inibidores de Metaloproteinases de Matriz , Modelos Moleculares , Relação Estrutura-Atividade , Suínos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese
18.
J Med Chem ; 45(23): 4954-7, 2002 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-12408705

RESUMO

New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TACE was built and examined to identify the S1' site as the key area for TACE selectivity over MMPs. Rational exploration of the P1'-S1' interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a TACE-selective P1' group. Further optimization led to the discovery of IK682 as a selective and orally bioavailable TACE inhibitor.


Assuntos
Ácidos Hidroxâmicos/síntese química , Lactamas/síntese química , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/síntese química , Proteínas ADAM , Proteína ADAM17 , Administração Oral , Animais , Disponibilidade Biológica , Cães , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Lactamas/química , Lactamas/farmacologia , Metaloproteinase 3 da Matriz/química , Modelos Moleculares , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Suínos
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