RESUMO
Historically, modulation of transforming growth factor ß (TGF-ß) signaling has been deemed a rational strategy to treat many disorders, though few successful examples have been reported to date. This difficulty could be partially attributed to the challenges of achieving good specificity over many closely related enzymes that are implicated in distinct phenotypes in organ development and in tissue homeostasis. Recently, fresolimumab and disitertide, two peptidic TGF-ß blockers, demonstrated significant therapeutic effects toward human skin fibrosis. Therefore, the selective blockage of TGF-ß signaling assures a viable treatment option for fibrotic skin disorders such as systemic sclerosis (SSc). In this report, we disclose selective TGF-ß type II receptor (TGF-ßRII) inhibitors that exhibited high functional selectivity in cell-based assays. The representative compound 29 attenuated collagen type I alpha 1 chain (COL1A1) expression in a mouse fibrosis model, which suggests that selective inhibition of TGF-ßRII-dependent signaling could be a new treatment for fibrotic disorders.
RESUMO
A series of N-substituted sulfonylamino-alkanecarboxylate ADAMTS-5 (Aggrecanase-2) inhibitors has been synthesized and the in vitro enzyme SAR is discussed. This report is the first example of carboxylate-based ADAMTS-5 inhibitors which show strong potency of IC(50)<0.1muM with excellent selectivity over MMP-1 and TACE.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores de Proteases/síntese química , Proteína ADAMTS5 , Ácidos Carboxílicos/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Osteoartrite/tratamento farmacológico , Inibidores de Proteases/farmacologia , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
A series of 1-sulfonylaminocyclopropanecarboxylates was synthesized as ADAMTS-5 (Aggrecanase-2) inhibitors. After an intensive investigation of the central cyclopropane core including its absolute stereochemistry and substituents, we found compound 22 with an Agg-2 IC50=7.4 nM, the most potent ADAMTS-5 inhibitor reported so far.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Ciclopropanos/síntese química , Inibidores de Proteases/síntese química , Sulfonamidas/síntese química , Proteínas ADAM/metabolismo , Proteína ADAMTS5 , Animais , Sítios de Ligação , Simulação por Computador , Ciclopropanos/química , Ciclopropanos/farmacocinética , Ciclopropanos/farmacologia , Desenho de Fármacos , Humanos , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Ligação Proteica , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
SCD1 is a rate-limiting enzyme in the conversion of saturated fatty acids to monounsaturated fatty acids. SCD1 inhibitors have potential effects on obesity, diabetes, acne, and cancer, but the adverse effects associated with SCD1 inhibition in the skin and eyelids are impediments to clinical development. To avoid mechanism-based adverse effects, we explored the compounds that selectively inhibit SCD1 in the liver in an ex vivo assay. Starting from a systemically active lead compound, we focused on the physicochemical properties tPSA and cLogP to minimize exposure in the off-target tissues. This effort led to the discovery of thiazole-4-acetic acid analog 48 as a potent and liver-selective SCD1 inhibitor. Compound 48 exhibited significant effects in rodent models of diabetes, hepatic steatosis, and obesity, with sufficient safety margins in a rat toxicology study with repeated dosing.
Assuntos
Ácido Acético/química , Ácido Acético/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Tiazóis/química , Tiazóis/farmacologia , Animais , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/enzimologia , Diabetes Mellitus/metabolismo , Descoberta de Drogas , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/enzimologia , Fígado Gorduroso/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/enzimologia , Obesidade/metabolismo , Ratos , Ratos Sprague-Dawley , Estearoil-CoA Dessaturase/metabolismoRESUMO
Inhibition of hypoxia inducible factor prolyl hydroxylase (PHD) represents a promising strategy for the discovery of a next generation treatment for renal anemia. We identified several 5,6-fused ring systems as novel scaffolds of the PHD inhibitor on the basis of pharmacophore analysis. In particular, triazolopyridine derivatives showed potent PHD2 inhibitory activities. Examination of the predominance of the triazolopyridines in potency by electrostatic calculations suggested favorable π-π stacking interactions with Tyr310. Lead optimization to improve the efficacy of erythropoietin release in cells and in vivo by improving cell permeability led to the discovery of JTZ-951 (compound 14), with a 5-phenethyl substituent on the triazolopyridine group, which increased hemoglobin levels with daily oral dosing in rats. Compound 14 was rapidly absorbed after oral administration and disappeared shortly thereafter, which could be advantageous in terms of safety. Compound 14 was selected as a clinical candidate.
RESUMO
A practical and adequate approach to modeling light propagation in an adult head with a low-scattering cerebrospinal fluid (CSF) region by use of diffusion theory was investigated. The diffusion approximation does not hold in a nonscattering or low-scattering regions. The hybrid radiosity-diffusion method was adopted to model the light propagation in the head with a nonscattering region. In the hybrid method the geometry of the nonscattering region is acquired as a priori information. In reality, low-level scattering occurs in the CSF region and may reduce the error caused by the diffusion approximation. The partial optical path length and the spatial sensitivity profile calculated by the finite-element method agree well with those calculated by the Monte Carlo method in the case in which the transport scattering coefficient of the CSF layer is greater than 0.3 mm(-1). Because it is feasible to assume that the transport scattering coefficient of a CSF layer is 0.3 mm(-1), it is practical to adopt diffusion theory to the modeling of light propagation in an adult head as an alternative to the hybrid method.
Assuntos
Líquido Cefalorraquidiano/citologia , Líquido Cefalorraquidiano/fisiologia , Cabeça/anatomia & histologia , Cabeça/fisiologia , Modelos Biológicos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Tomografia Óptica/métodos , Anisotropia , Mapeamento Encefálico/métodos , Simulação por Computador , Humanos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Luz , Reprodutibilidade dos Testes , Espalhamento de Radiação , Sensibilidade e EspecificidadeRESUMO
Protein kinase C (PKC) is a family of enzymes, which play important roles in intracellular signal transduction. We have designed novel PKC ligands having an isobenzofuranone template, based on the proposed interaction of DAG (1,2-diacyl-sn-glycerol) with the PKCdelta C1B ligand-binding domain. Several isobenzofuranone derivatives were synthesized and their PKCalpha binding activities were evaluated. The pivaloyl derivative 1f was found to be a strong PKCalpha ligand, and the structure-activity relationship is well explained by our proposed binding model.
Assuntos
Benzofuranos/farmacologia , Proteína Quinase C/antagonistas & inibidores , Benzofuranos/síntese química , Sítios de Ligação , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio , Ligantes , Estrutura Molecular , Ligação Proteica , Proteína Quinase C/química , Relação Estrutura-AtividadeRESUMO
Protein kinase C (PKC) is a family of enzymes, which play important roles in intracellular signal transduction. To examine the distance between the two ligand binding sites (C1A and C1B) of PKC, we designed and synthesized two series of isobenzofuranone dimers. Peak binding activities were observed for the C3-acyl chain dimers having a C10-C12 linker and for the C7 dimers having a C14-C16.