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1.
Chem Res Toxicol ; 24(2): 269-78, 2011 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-21288051

RESUMO

Isopropyl 9-anti-[5-cyano-6-(2-methyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-3-oxa-7-aza-bicyclo[3.3.1]nonane-7-carboxylate (1) represents a prototypic compound from a lead chemical series of G protein-coupled receptor 119 agonists, intended for treatment of type 2 diabetes. When compound 1 was incubated with NADPH-supplemented human liver microsomes in the presence of glutathione, two thioether conjugates M4-1 and M5-1 were observed. Omission of NADPH from the microsomal incubations prevented the formation of M5-1 but not M4-1. The formation of M4-1 was also discerned in incubations of 1 and glutathione with human liver cytosol, partially purified glutathione transferase, and in phosphate buffer at pH 7.4. M4-1 was isolated, and its structure ascertained from LC-MS/MS and NMR analysis. The mass spectral and NMR data suggested that M4-1 was obtained from a nucleophilic displacement of the 6-(2-methylpyridin-3-yloxy) group in 1 by glutathione. In addition, mass spectral studies revealed that M5-1 was derived from an analogous displacement reaction on a monohydroxylated metabolite of 1; the regiochemistry of hydroxylation was established to be on the isopropyl group. Of great interest were the findings that replacement of the 5-cyano group in 1 with a 5-methyl group resulted in 2, which was practically inert toward reaction with glutathione. This observation suggests that the electron-withdrawing potential of the C5 cyano group serves to increase the electrophilicity of the C6 carbon (via stabilization of the transition state) and favors reaction with the nucleophilic thiol. The mechanistic insights gained from these studies should assist medicinal chemistry efforts toward the design of analogs that retain primary pharmacology but are latent toward reaction with biological nucleophiles, thus mitigating the potential for toxicological outcome due to adduction with glutathione or proteins.


Assuntos
Glutationa/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Pirimidinas/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glutationa/química , Cavalos , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Pirimidinas/química
2.
J Med Chem ; 61(3): 1130-1152, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29298069

RESUMO

Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Ciclobutanos/farmacologia , Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Sulfonamidas/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Ciclobutanos/química , Ciclobutanos/farmacocinética , Ciclobutanos/uso terapêutico , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Janus Quinase 1/química , Janus Quinase 2/antagonistas & inibidores , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Pirróis/química , Pirróis/farmacocinética , Pirróis/uso terapêutico , Ratos , Especificidade por Substrato , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Distribuição Tecidual
3.
J Med Chem ; 60(13): 5349-5363, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28375629

RESUMO

Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB binding protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization that paid particular attention to physiochemical properties delivered chemical probes with desirable potency, selectivity, and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein).


Assuntos
Proteína de Ligação a CREB/antagonistas & inibidores , Desenho de Fármacos , Proteína p300 Associada a E1A/antagonistas & inibidores , Morfolinas/farmacologia , Proteína de Ligação a CREB/metabolismo , Química Farmacêutica , Relação Dose-Resposta a Droga , Proteína p300 Associada a E1A/metabolismo , Humanos , Estrutura Molecular , Morfolinas/síntese química , Morfolinas/química , Relação Estrutura-Atividade
4.
Chem Biol ; 22(12): 1588-96, 2015 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-26670081

RESUMO

Bromodomains are involved in transcriptional regulation through the recognition of acetyl lysine modifications on diverse proteins. Selective pharmacological modulators of bromodomains are lacking, although the largely hydrophobic nature of the pocket makes these modules attractive targets for small-molecule inhibitors. This work describes the structure-based design of a highly selective inhibitor of the CREB binding protein (CBP) bromodomain and its use in cell-based transcriptional profiling experiments. The inhibitor downregulated a number of inflammatory genes in macrophages that were not affected by a selective BET bromodomain inhibitor. In addition, the CBP bromodomain inhibitor modulated the mRNA level of the regulator of G-protein signaling 4 (RGS4) gene in neurons, suggesting a potential therapeutic opportunity for CBP inhibitors in the treatment of neurological disorders.


Assuntos
Proteína de Ligação a CREB/antagonistas & inibidores , Desenho de Fármacos , Bibliotecas de Moléculas Pequenas/química , Proteína de Ligação a CREB/genética , Transferência Ressonante de Energia de Fluorescência , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Estrutura Terciária de Proteína , Proteínas RGS/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Transcriptoma
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