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1.
J Med Chem ; 62(20): 8953-8972, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31314518

RESUMO

As a member of the Janus (JAK) family of nonreceptor tyrosine kinases, TYK2 plays an important role in mediating the signaling of pro-inflammatory cytokines including IL-12, IL-23, and type 1 interferons. The nicotinamide 4, identified by a SPA-based high-throughput screen targeting the TYK2 pseudokinase domain, potently inhibits IL-23 and IFNα signaling in cellular assays. The described work details the optimization of this poorly selective hit (4) to potent and selective molecules such as 47 and 48. The discoveries described herein were critical to the eventual identification of the clinical TYK2 JH2 inhibitor (see following report in this issue). Compound 48 provided robust inhibition in a mouse IL-12-induced IFNγ pharmacodynamic model as well as efficacy in an IL-23 and IL-12-dependent mouse colitis model. These results demonstrate the ability of TYK2 JH2 domain binders to provide a highly selective alternative to conventional TYK2 orthosteric inhibitors.

2.
J Med Chem ; 62(20): 8973-8995, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31318208

RESUMO

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.

3.
Sci Transl Med ; 11(502)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31341059

RESUMO

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.

4.
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 Drogas , 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
5.
J Med Chem ; 58(10): 4278-90, 2015 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-25905990

RESUMO

An empirical approach to improve the microsomal stability and CYP inhibition profile of lead compounds 1a and 1b led to the identification of 5 (BMS-341) as a dissociated glucocorticoid receptor modulator. Compound 5 showed significant improvements in pharmacokinetic properties and, unlike compounds 1a-b, displayed a linear, dose-dependent pharmacokinetic profile in rats. When tested in a chronic model of adjuvant-induced arthritis in rat, the ED50 of 5 (0.9 mg/kg) was superior to that of both 1a and 1b (8 and 17 mg/kg, respectively).


Assuntos
Artrite Experimental/tratamento farmacológico , Inibidores das Enzimas do Citocromo P-450/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Receptores de Glucocorticoides/metabolismo , Tiadiazóis/farmacologia , Animais , Sangue/efeitos dos fármacos , Sangue/metabolismo , Técnicas de Química Sintética , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Estabilidade de Medicamentos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Masculino , Ratos Endogâmicos Lew , Receptores de Glucocorticoides/agonistas , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/farmacocinética , Fator de Transcrição AP-1/metabolismo
6.
J Biol Chem ; 290(17): 11061-74, 2015 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-25762719

RESUMO

Inhibition of signal transduction downstream of the IL-23 receptor represents an intriguing approach to the treatment of autoimmunity. Using a chemogenomics approach marrying kinome-wide inhibitory profiles of a compound library with the cellular activity against an IL-23-stimulated transcriptional response in T lymphocytes, a class of inhibitors was identified that bind to and stabilize the pseudokinase domain of the Janus kinase tyrosine kinase 2 (Tyk2), resulting in blockade of receptor-mediated activation of the adjacent catalytic domain. These Tyk2 pseudokinase domain stabilizers were also shown to inhibit Tyk2-dependent signaling through the Type I interferon receptor but not Tyk2-independent signaling and transcriptional cellular assays, including stimulation through the receptors for IL-2 (JAK1- and JAK3-dependent) and thrombopoietin (JAK2-dependent), demonstrating the high functional selectivity of this approach. A crystal structure of the pseudokinase domain liganded with a representative example showed the compound bound to a site analogous to the ATP-binding site in catalytic kinases with features consistent with high ligand selectivity. The results support a model where the pseudokinase domain regulates activation of the catalytic domain by forming receptor-regulated inhibitory interactions. Tyk2 pseudokinase stabilizers, therefore, represent a novel approach to the design of potent and selective agents for the treatment of autoimmunity.


Assuntos
Modelos Moleculares , Transdução de Sinais , Linfócitos T/enzimologia , TYK2 Quinase/química , Cristalografia por Raios X , Estabilidade Enzimática , Humanos , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Janus Quinase 3/genética , Janus Quinase 3/metabolismo , Estrutura Terciária de Proteína , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/metabolismo , Receptores de Trombopoetina/genética , Receptores de Trombopoetina/metabolismo , TYK2 Quinase/genética
7.
Bioorg Med Chem Lett ; 24(15): 3268-73, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24980053

RESUMO

Acylureas and acyclic imides are found to be excellent isosteres for 2-acylamino-1,3,4-thiadiazole in the azaxanthene-based series of glucocorticoid receptor (GR) agonists. The results reported herein show that primary acylureas maintain high affinity and selectivity for GR while providing improved CYP450 inhibition and pharmacokinetic profile over 2-acylamino-1,3,4-thiadiazoles. General methods for synthesis of a variety of acylureas and acyclic imides from a carboxylic acid were utilized and are described.


Assuntos
Descoberta de Drogas , Compostos Heterocíclicos com 3 Anéis/farmacologia , Receptores de Glucocorticoides/agonistas , Tiadiazóis/farmacologia , Ureia/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Tiadiazóis/química , Ureia/análogos & derivados , Ureia/química
8.
J Med Chem ; 54(20): 7318-33, 2011 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-21899328

RESUMO

Structurally novel 5H-chromeno[2,3-b]pyridine (azaxanthene) selective glucocorticoid receptor (GR) modulators have been identified. A screening paradigm utilizing cellular assays of GR-mediated transrepression of proinflammatory transcription factors and transactivation of GR-dependent genes combined with three physiologically relevant assays of cytokine induction in human whole blood has allowed for the identification of high affinity, selective GR ligands that display a broad range of pharmacological profiles. Agonist efficacy in reporter assays can be tuned by halogenation of a pendent phenyl ring and correlates well with efficacy for cytokine inhibition in human whole blood. A hypothetical binding mode is proposed, invoking an expanded ligand binding pocket resembling that of arylpyrazole-bound GR structures. Two compounds of close structural similarity (35 and 37; BMS-776532 and BMS-791826, respectively) have been found to maintain distinct and consistent levels of partial agonist efficacy across several assays, displaying anti-inflammatory activity comparable to that of prednisolone 2 in suppressing cytokine production in whole blood and in rodent models of acute and chronic inflammation.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Receptores de Glucocorticoides/agonistas , Tiadiazóis/síntese química , Fosfatase Alcalina/biossíntese , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Linhagem Celular Tumoral , Agonismo Parcial de Drogas , Edema/tratamento farmacológico , Glutamato-Amônia Ligase/biossíntese , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Técnicas In Vitro , Interleucina-1beta/sangue , Masculino , Modelos Moleculares , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Elementos de Resposta , Estereoisomerismo , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/farmacologia , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Ativação Transcricional , Fator de Necrose Tumoral alfa/sangue , Tirosina Transaminase/biossíntese
9.
Bioorg Med Chem Lett ; 21(14): 4141-5, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21696952

RESUMO

A series of inhibitors of mammalian 15-lipoxygenase (15-LO) based on a 3,4,5-tri-substituted pyrazole scaffold is described. Replacement of a sulfonamide functionality in the lead series with a sulfamide group resulted in improved physicochemical properties generating analogs with enhanced inhibition in cell-based and whole blood assays.


Assuntos
Amidas/química , Araquidonato 15-Lipoxigenase/química , Inibidores de Lipoxigenase/química , Pirazóis/química , Amidas/síntese química , Amidas/farmacologia , Animais , Araquidonato 15-Lipoxigenase/metabolismo , Células CHO , Cricetinae , Cricetulus , Humanos , Ácidos Hidroxieicosatetraenoicos/sangue , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacologia , Coelhos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
10.
J Med Chem ; 53(23): 8241-51, 2010 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-21073190

RESUMO

A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.


Assuntos
Amidas/farmacologia , Receptores de Glucocorticoides/agonistas , Amidas/química , Animais , Modelos Moleculares , Ratos
11.
Bioorg Med Chem Lett ; 19(8): 2139-43, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19321341

RESUMO

A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising dissociation profile in discriminating between transrepression and transactivation activities. 17a is a partial agonist of GR-mediated transactivation which elicits potent and efficacious transrepression in reporter gene assays. A hypothetical binding mode is provided which accounts for the induction of functional activity by a bridgehead methyl group.


Assuntos
Antracenos/farmacologia , Descoberta de Drogas , Receptores de Glucocorticoides/metabolismo , Antracenos/química , Linhagem Celular , Cristalografia por Raios X , Descoberta de Drogas/métodos , Glucocorticoides/química , Glucocorticoides/farmacologia , Humanos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/fisiologia , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 17(18): 5115-20, 2007 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17656086

RESUMO

A series of 2,4,5-tri-substituted imidazoles has proven to be highly potent in inhibiting mammalian 15-lipoxygenase (15-LO) with excellent selectivity over human isozymes 5- and P-12-LO. Non-symmetrical sulfamides (e.g., 21a-n) were found to be suitable replacements for the earlier arylsulfonamide-containing members of this series (e.g., 2, 14a-p). Several members of these series also demonstrated potent inhibition of human 15-LO in a cell-based assay.


Assuntos
Imidazóis/farmacologia , Inibidores de Lipoxigenase , Inibidores de Lipoxigenase/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Imidazóis/química , Inibidores de Lipoxigenase/química , Masculino , Ratos , Ratos Sprague-Dawley
13.
Bioorg Med Chem Lett ; 15(5): 1435-40, 2005 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-15713402

RESUMO

A series of inhibitors of mammalian 15-lipoxygenase based on tryptamine and homotryptamine scaffolds is described. Compounds with aryl substituents at C-2 of the indole core of tryptamine and homotryptamine sulfonamides (e.g., 37a-p) proved to be potent inhibitors of the isolated enzyme. Selected compounds also demonstrated desirable inhibition selectivities over isozymes 5- and P-12-LO.


Assuntos
Inibidores Enzimáticos/farmacologia , Inibidores de Lipoxigenase , Sulfonamidas/farmacologia , Triptaminas/química , Animais , Inibidores Enzimáticos/química , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química
14.
Bioorg Med Chem Lett ; 14(1): 177-80, 2004 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-14684323

RESUMO

Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability.


Assuntos
Proteínas de Transporte de Cátions/antagonistas & inibidores , Guanidinas/administração & dosagem , Imidazóis/administração & dosagem , Proteínas de Membrana/antagonistas & inibidores , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Administração Oral , Disponibilidade Biológica , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular , Guanidinas/química , Guanidinas/farmacocinética , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Proteínas de Membrana/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Trocador 1 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/metabolismo , Estereoisomerismo
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