RESUMO
A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFß receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFß induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.
Assuntos
Cicatriz/prevenção & controle , Descoberta de Drogas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Pele/efeitos dos fármacos , Animais , Modelos Moleculares , Fosforilação , Ratos , Receptor do Fator de Crescimento Transformador beta Tipo IRESUMO
A series of pantolactam based compounds were identified as potent antagonists for the androgen receptor (AR). Those that possessed properties suitable for topical delivery were evaluated in the validated Hamster Ear Model. Several compounds were found to be efficacious in reducing wax esters, a major component of sebum, initiating further preclinical work on these compounds.
Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Ésteres/metabolismo , Lactamas/farmacologia , Sebo/efeitos dos fármacos , Ceras/metabolismo , Administração Tópica , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/química , Animais , Cricetinae , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ésteres/química , Lactamas/síntese química , Lactamas/química , Modelos Animais , Modelos Moleculares , Estrutura Molecular , Receptores Androgênicos/metabolismo , Sebo/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Ceras/químicaRESUMO
A series of acyloxyalkyl and amidooxyalkyl ketones appended to a carbobenzyloxy aspartic acid core have been prepared. The most potent of these new inhibitors was 4i with a K(i) of 0.5 microM. These two series provide an improved understanding of the binding requirements for the hydrophobic prime side of ICE.
Assuntos
Inibidores de Caspase , Inibidores de Cisteína Proteinase/farmacologia , Cetonas/farmacologia , Humanos , Modelos Moleculares , Monócitos/efeitos dos fármacosRESUMO
Succinic acid amides have been found to be effective P2-P3 scaffold replacements for peptidic ICE inhibitors. Heteroarylalkyl fragments occupying the P4 position provided access to compounds with nM affinities. Utilization of an acylal prodrug moiety was required to overcome biopharmaceutical issues which led to the identification of 17f, a potential clinical candidate.
Assuntos
Amidas/química , Inibidores de Caspase , Inibidores de Cisteína Proteinase/farmacologia , Ácido Succínico/química , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacocinética , Meia-Vida , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel nonsteroidal androgen receptor antagonist, (R)-4-(1-benzyl-4,4-dimethyl-2-oxopyrrolidin-3-yloxy)-2-(trifluoromethyl)benzonitrile (1), for the topical control of sebum production is reported. This compound, which is potent, selective, and efficacious in the clinically validated golden Syrian hamster ear animal model, was designed to be delivered to the pilosebaceous unit, the site of action, preferentially by the follicular route.
Assuntos
Antagonistas de Receptores de Andrógenos , Desenho de Fármacos , Folículo Piloso , Nitrilas/administração & dosagem , Nitrilas/farmacologia , Sebo/efeitos dos fármacos , Sebo/metabolismo , Administração Tópica , Animais , Fenômenos Químicos , Cricetinae , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Masculino , Mesocricetus , Nitrilas/metabolismo , Nitrilas/farmacocinéticaRESUMO
A series of diphenyl ethers was prepared and evaluated for androgen receptor antagonist activity in human androgen receptor binding and cellular functional assays. Analogs with potent in vitro activities were evaluated for topical in vivo efficacy in the Golden Syrian Hamster ear model. Several compounds showed reduction in wax esters in this validated animal model.
Assuntos
Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/química , Antagonistas de Receptores de Andrógenos , Éteres Fenílicos/administração & dosagem , Éteres Fenílicos/síntese química , Sebo/efeitos dos fármacos , Sebo/metabolismo , Administração Tópica , Animais , Linhagem Celular Tumoral , Cricetinae , Humanos , Masculino , Mesocricetus , Receptores Androgênicos/química , Reprodutibilidade dos TestesRESUMO
The first examples of thioether-substituted benzonitriles as potential soft-drug androgen receptor antagonists are reported. A number of 4-(alkylthio)- and of 4-(arylthio)-benzonitrile analogs were evaluated in human androgen receptor binding and cellular functional assays. Analogs with potent in vitro binding and cellular activities were evaluated for topical in vivo efficacy in the Golden Syrian hamster ear model. Analogs from both the 4-(alkylthio)- and of 4-(arylthio)-benzonitrile series showed moderate reduction of wax esters in vivo.
Assuntos
Antagonistas de Androgênios/química , Antagonistas de Receptores de Andrógenos , Nitrilas/síntese química , Nitrilas/farmacologia , Sebo/efeitos dos fármacos , Sebo/metabolismo , Antagonistas de Androgênios/farmacologia , Animais , Linhagem Celular , Cricetinae , Humanos , Insetos , Masculino , Mesocricetus , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Receptores Androgênicos/metabolismoRESUMO
A series of amino-pyridines were synthesized and evaluated for androgen antagonist activities. Among these compounds, (R)-(+)-6-[methyl-(1-phenyl-ethyl)-amino]-4-trifluoromethyl-nicotinonitrile was the most active example of this class. This compound displayed potent androgen receptor antagonist activity as well as favorable pharmacokinetic characteristics for a potential topical agent. It also demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.
Assuntos
Aminopiridinas/química , Aminopiridinas/farmacologia , Antagonistas de Receptores de Andrógenos , Cabelo/efeitos dos fármacos , Cabelo/crescimento & desenvolvimento , Sebo/efeitos dos fármacos , Sebo/metabolismo , Aminopiridinas/síntese química , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C3H , Modelos Moleculares , Estrutura Molecular , Receptores Androgênicos/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of substituted 4-aryl-2-trifluoromethylbenzonitrile analogs were evaluated in the human androgen receptor binding and cellular functional assays. Analogs with sufficient in vitro binding and cellular potency (IC(50)<200 nM) were tested in the progesterone receptor binding assay for selectivity and in the Golden Syrian hamster ear model for in vivo efficacy. Within the series, compound 4 e was identified to be the most active analog in vivo (wax ester inhibition=86%).
Assuntos
Antagonistas de Receptores de Andrógenos , Flúor/química , Nitrilas/química , Nitrilas/farmacologia , Receptores Androgênicos/metabolismo , Sebo/efeitos dos fármacos , Sebo/metabolismo , Humanos , Concentração Inibidora 50 , Metilação , Estrutura Molecular , Nitrilas/síntese química , Relação Estrutura-AtividadeRESUMO
Synthesis, pharmacology, and pharmacokinetic profiles of (1R, 2S)-4-(2-cyano-cyclohexyl-oxy)-2-trifluoromethyl-benzonitrile are reported. This compound demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.
Assuntos
Antagonistas de Androgênios/farmacologia , Cabelo/crescimento & desenvolvimento , Hidrocarbonetos Fluorados/farmacologia , Nitrilas/farmacologia , Sebo , Animais , Cricetinae , Hidrocarbonetos Fluorados/farmacocinética , Masculino , Mesocricetus , Camundongos , Modelos Moleculares , Nitrilas/farmacocinéticaRESUMO
The inhibition of the cytosolic isoenzyme BCAT that is expressed specifically in neuronal tissue is likely to be useful for the treatment of neurodegenerative and other neurological disorders where glutamatergic mechanisms are implicated. Compound 2 exhibited an IC50 of 0.8 microM in the hBCATc assays; it is an active and selective inhibitor. Inhibitor 2 also blocked calcium influx into neuronal cells following inhibition of glutamate uptake, and demonstrated neuroprotective efficacy in vivo. SAR, pharmacology, and the crystal structure of hBCATc with inhibitor 2 are described.
Assuntos
Benzofuranos/síntese química , Benzofuranos/uso terapêutico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Sulfonamidas/síntese química , Sulfonamidas/uso terapêutico , Transaminases/antagonistas & inibidores , Animais , Benzofuranos/química , Cálcio/antagonistas & inibidores , Cálcio/metabolismo , Células Cultivadas , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Ácido Glutâmico/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Humanos , Técnicas In Vitro , Modelos Moleculares , Estrutura Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
A series of sulfonamides (1) has been prepared as inhibitors of interleukin-1beta converting enzyme (ICE), also known as caspase 1. These compounds were designed to improve potency by rigidifying the enzyme bound molecule through an intramolecular hydrogen bond. An X-ray crystal structure of a representative member of this series bound to the active site of ICE, confirms the presence of the hydrogen bonding interaction.
Assuntos
Inibidores de Caspase , Desenho de Fármacos , Serpinas/síntese química , Serpinas/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Proteínas Virais , Sítios de Ligação , Caspase 1/metabolismo , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A novel class of reversible inhibitors of Interleukin-1beta-converting enzyme (ICE, caspase-1) were discovered by iterative structure-based design. Guided by the X-ray crystal structure of analogues 1, 7 and 10 bound to ICE, we have designed a nonpeptide series of small molecule inhibitors. These compounds incorporate an arylsulfonamide moiety which replaces Val-His unit (P3-P2 residues) amino acids of the native substrate. The synthesis of the core structure, structure-activity relationships (SARs), and proposed binding orientation based on molecular modeling studies for this series of ICE inhibitors are described.