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1.
Bioorg Med Chem Lett ; 26(10): 2470-2474, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27055941

RESUMO

The synthesis and structure-activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Lisofosfolipídeos/agonistas , Esfingosina/análogos & derivados , Relação Estrutura-Atividade , Administração Oral , Animais , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Contagem de Linfócitos , Masculino , Ratos Endogâmicos Lew , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/agonistas
2.
J Med Chem ; 59(6): 2820-40, 2016 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-26924461

RESUMO

Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P1-5) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P1, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P1. Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.


Assuntos
Isoxazóis/síntese química , Isoxazóis/farmacologia , Lisofosfolipídeos/agonistas , Esfingosina/análogos & derivados , Animais , Artrite Experimental/tratamento farmacológico , Células CHO , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cricetinae , Cricetulus , Descoberta de Drogas , Encefalomielite Autoimune Experimental/tratamento farmacológico , Humanos , Imunossupressores/síntese química , Imunossupressores/farmacologia , Sistema Linfático/citologia , Sistema Linfático/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos Lew , Esfingosina/agonistas , Relação Estrutura-Atividade , Timo/citologia , Timo/efeitos dos fármacos
3.
J Med Chem ; 58(19): 7775-84, 2015 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-26359680

RESUMO

In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug 2 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug 1 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of 1 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, 2 demonstrated similar efficacy to 1. Most importantly, it was shown in clinical studies that prodrug 2 was indeed effective in addressing the pH-dependent absorption issue associated with 1.


Assuntos
Organofosfatos/farmacologia , Fenilacetatos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Artrite Experimental/tratamento farmacológico , Disponibilidade Biológica , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Macaca fascicularis , Masculino , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Estrutura Molecular , Organofosfatos/química , Fenilacetatos/química , Pró-Fármacos/farmacocinética , Inibidores de Proteínas Quinases/química , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-Atividade
4.
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
5.
Proc Natl Acad Sci U S A ; 111(33): 12163-8, 2014 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-25092323

RESUMO

The RAR-related orphan receptor gamma t (RORγt) is a nuclear receptor required for generating IL-17-producing CD4(+) Th17 T cells, which are essential in host defense and may play key pathogenic roles in autoimmune diseases. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol and lipid metabolism. Here, we describe the identification of several naturally occurring oxysterols as RORγt agonists. The most potent and selective activator for RORγt is 7ß, 27-dihydroxycholesterol (7ß, 27-OHC). We show that these oxysterols reverse the inhibitory effect of an RORγt antagonist, ursolic acid, in RORγ- or RORγt-dependent cell-based reporter assays. These ligands bind directly to recombinant RORγ ligand binding domain (LBD), promote recruitment of a coactivator peptide, and reduce binding of a corepressor peptide to RORγ LBD. In primary cells, 7ß, 27-OHC and 7α, 27-OHC enhance the differentiation of murine and human IL-17-producing Th17 cells in an RORγt-dependent manner. Importantly, we showed that Th17, but not Th1 cells, preferentially produce these two oxysterols. In vivo, administration of 7ß, 27-OHC in mice enhanced IL-17 production. Mice deficient in CYP27A1, a key enzyme in generating these oxysterols, showed significant reduction of IL-17-producing cells, including CD4(+) and γδ(+) T cells, similar to the deficiency observed in RORγt knockout mice. Our results reveal a previously unknown mechanism for selected oxysterols as immune modulators and a direct role for CYP27A1 in generating these RORγt agonist ligands, which we propose as RORγt endogenous ligands, driving both innate and adaptive IL-17-dependent immune responses.


Assuntos
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Esteróis/farmacologia , Células Th17/citologia , Animais , Diferenciação Celular , Colestanotriol 26-Mono-Oxigenase/metabolismo , Interleucina-17/biossíntese , Ligantes , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Esteróis/metabolismo
6.
Bioorg Med Chem Lett ; 23(14): 4120-6, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23746475

RESUMO

A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38ß isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Sítios de Ligação , Cristalografia por Raios X , Humanos , Ligações de Hidrogênio , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Simulação de Dinâmica Molecular , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 23(10): 3028-33, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23578688

RESUMO

A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38α inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and α-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2mpk (equivalent to 10mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10mpk of 1 itself. At a suspension dose of 142mpk (equivalent to 100mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of 1. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates.


Assuntos
Dacarbazina/análogos & derivados , Pró-Fármacos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Triazinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Cristalografia por Raios X , Dacarbazina/química , Relação Dose-Resposta a Droga , Concentração de Íons de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Pirróis/administração & dosagem , Pirróis/síntese química , Ratos , Solubilidade , Relação Estrutura-Atividade , Temperatura Ambiente , Triazinas/administração & dosagem , Triazinas/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Bioorg Med Chem Lett ; 21(23): 7006-12, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22018461

RESUMO

The synthesis, structure-activity relationships (SAR), and biological results of pyridyl-substituted azaindole based tricyclic inhibitors of IKK2 are described. Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease.


Assuntos
Acetamidas/química , Descoberta de Drogas , Inibidores Enzimáticos/química , Compostos Heterocíclicos com 3 Anéis/química , Quinase I-kappa B/antagonistas & inibidores , Acetamidas/síntese química , Acetamidas/farmacologia , Administração Oral , Animais , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 21(15): 4633-7, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21705217
11.
Bioorg Med Chem Lett ; 20(23): 6886-9, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21035336

RESUMO

The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno/química , Inibidores de Proteínas Quinases/síntese química , Pirazóis/farmacologia , Animais , Cristalografia por Raios X , Camundongos , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese
12.
J Med Chem ; 53(18): 6629-39, 2010 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-20804198

RESUMO

The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp(2) character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Pirróis/síntese química , Triazinas/síntese química , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Disponibilidade Biológica , Células CACO-2 , Cristalografia por Raios X , Feminino , Humanos , Ligações de Hidrogênio , Técnicas In Vitro , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/química , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Triazinas/farmacocinética , Triazinas/farmacologia , Fator de Necrose Tumoral alfa/biossíntese
13.
Bioorg Med Chem Lett ; 20(19): 5864-8, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20732813

RESUMO

The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38 α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Nitrogênio/química , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/química , Enxofre/química , Tiazóis/química , Sítios de Ligação , Cristalografia por Raios X , Desenho de Drogas , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia
14.
J Med Chem ; 53(9): 3814-30, 2010 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-20405922

RESUMO

Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure-activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.


Assuntos
Hidantoínas/farmacocinética , Fatores Imunológicos/química , Antígeno-1 Associado à Função Linfocitária/efeitos dos fármacos , Ácidos Nicotínicos/farmacocinética , Humanos , Hidantoínas/farmacologia , Antígeno-1 Associado à Função Linfocitária/química , Antígeno-1 Associado à Função Linfocitária/imunologia , Ácidos Nicotínicos/toxicidade , Relação Estrutura-Atividade
15.
J Immunol ; 184(7): 3917-26, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20190141

RESUMO

LFA-1 appears to play a central role in normal immune responses to foreign Ags. In autoimmune or inflammatory diseases, there is increased expression of LFA-1 and/or its counterligand, ICAM-1. Others have demonstrated that the targeted disruption of LFA-1:ICAM interactions, either by gene deletion or Ab treatment in mice, results in reduced leukocyte trafficking, inflammatory responses, and inhibition of inflammatory arthritis in the K/BxN serum transfer model. However, there has been little success in finding a small-molecule LFA-1 antagonist that can similarly impact rodent models of arthritis. In this paper, we present the first reported example of an LFA-1 small-molecule antagonist, BMS-587101, that is efficacious in preclinical disease models. In vitro, BMS-587101 inhibited LFA-1-mediated adhesion of T cells to endothelial cells, T cell proliferation, and Th1 cytokine production. Because BMS-587101 exhibits in vitro potency, cross-reactivity, and oral bioavailability in rodents, we evaluated the impact of oral administration of this compound in two different models of arthritis: Ab-induced arthritis and collagen-induced arthritis. Significant impact of BMS-587101 on clinical score in both models was observed, with inhibition comparable or better than anti-mouse LFA-1 Ab. In addition, BMS-587101 significantly reduced cytokine mRNA levels in the joints of Ab-induced arthritis animals as compared with those receiving vehicle alone. In paws taken from the collagen-induced arthritis study, the bones of vehicle-treated mice had extensive inflammation and bone destruction, whereas treatment with BMS-587101 resulted in marked protection. These findings support the potential use of an LFA-1 small-molecule antagonist in rheumatoid arthritis, with the capacity for disease modification.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Inflamação/tratamento farmacológico , Antígeno-1 Associado à Função Linfocitária/metabolismo , Compostos de Espiro/farmacologia , Tiofenos/farmacologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/biossíntese , Citocinas/efeitos dos fármacos , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Humanos , Inflamação/imunologia , Inflamação/patologia , Teste de Cultura Mista de Linfócitos , Antígeno-1 Associado à Função Linfocitária/imunologia , Camundongos
17.
J Med Chem ; 52(7): 1994-2005, 2009 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-19267461

RESUMO

The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IkappaB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.


Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Quinase I-kappa B/antagonistas & inibidores , Imidazóis/síntese química , Oxazóis/síntese química , Tiazóis/síntese química , Animais , Cristalografia por Raios X , Feminino , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Quinase I-kappa B/genética , Imidazóis/farmacocinética , Imidazóis/farmacologia , Técnicas In Vitro , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Oxazóis/farmacocinética , Oxazóis/farmacologia , Ratos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Fator de Necrose Tumoral alfa/biossíntese
19.
Bioorg Med Chem Lett ; 18(8): 2739-44, 2008 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-18364256

RESUMO

A novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38 alpha MAP kinase inhibitors. The synthesis, structure-activity relationships (SAR), and in vivo activity of selected analogs from this class of inhibitors are reported. Additional studies based on X-ray co-crystallography have revealed that one of the potent inhibitors from this series binds to the DFG-out conformation of the p38 alpha enzyme.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirróis/química , Triazinas/síntese química , Triazinas/farmacologia , Amidas/química , Animais , Cristalografia por Raios X , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Triazinas/química , Fator de Necrose Tumoral alfa/biossíntese
20.
Bioorg Med Chem Lett ; 18(8): 2652-7, 2008 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-18359226

RESUMO

The synthesis and structure-activity relationships (SAR) of p38 alpha MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38 alpha MAP kinase with excellent cellular potency toward the inhibition of TNFalpha production. Compound 2x was highly efficacious in vivo in inhibiting TNFalpha production in an acute murine model of TNFalpha production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38 alpha is also disclosed.


Assuntos
Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/química
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