RESUMO
Targeting nuclear receptor RORγ is recognized to be beneficial in multiple autoimmune disorders. We disclosed new indole analogues as potent RORγ inverse agonists. RO-2 as one of the potent and orally bioavailable compounds was evaluated in various models of autoimmune disorder. It showed potent suppression of downstream markers of RORγt activity in murine and human primary cells, ex vivo PD assay and in multiple animal models of autoimmune diseases. The results indicate the potential of these indole analogues as orally bioavailable small molecule inverse agonists of RORγt, efficacious in various Th17 driven models of autoimmune disorders.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Indóis/química , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Animais , Humanos , Camundongos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
In a pursuit to identify reversible and selective BTK inhibitors, two series based on 7H-pyrrolo[2,3-d]pyrimidine and 1H-pyrrolo[2,3-b]pyridine as the hinge binding core, have been identified. Structure activity relationship (SAR) exploration led to identification of two advanced lead molecules, 11 and 13, which demonstrated desired BTK inhibitory potency in different cellular assays, excellent selectivity in a panel of 50 diverse kinases, favorable in vivo PK properties in mice and anti-arthritic effect in a mouse model of CIA.
Assuntos
Antirreumáticos/química , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridinas/química , Piridinas/uso terapêutico , Pirróis/química , Pirróis/uso terapêutico , Tirosina Quinase da Agamaglobulinemia , Animais , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Reumatoide/enzimologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/metabolismo , Piridinas/farmacocinética , Piridinas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Relação Estrutura-AtividadeRESUMO
Chemokine receptor 9 (CCR9), a cell surface chemokine receptor which belongs to the G protein-coupled receptor, 7-trans-membrane superfamily, is expressed on lymphocytes in the circulation and is the key chemokine receptor that enables these cells to target the intestine. It has been proposed that CCR9 antagonism represents a means to prevent the aberrant immune response of inflammatory bowel disease in a localized and disease specific manner and one which is accessible to small molecule approaches. One possible reason why clinical studies with vercirnon, a prototype CCR9 antagonist, were not successful may be due to a relatively poor pharmacokinetic (PK) profile for the molecule. We wish to describe work aimed at producing new, orally active CCR9 antagonists based on the 1,3-dioxoisoindoline skeleton. This study led to a number of compounds that were potent in the nanomolar range and which, on optimization, resulted in several possible preclinical development candidates with excellent PK properties.
Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Isoindóis/química , Receptores CCR/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Técnicas de Química Sintética , Quimiotaxia/efeitos dos fármacos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Isoindóis/administração & dosagem , Isoindóis/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Receptores CCR/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMO
This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.
Assuntos
Antineoplásicos/síntese química , Benzazepinas/síntese química , Proteínas de Ciclo Celular/antagonistas & inibidores , Lactamas/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Tionas/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzazepinas/farmacocinética , Benzazepinas/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactamas/farmacocinética , Lactamas/farmacologia , Camundongos , Camundongos Nus , Mitose , Modelos Moleculares , Transplante de Neoplasias , Conformação Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tionas/farmacocinética , Tionas/farmacologia , Transplante Heterólogo , Quinase 1 Polo-LikeRESUMO
Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.
Assuntos
Antineoplásicos/síntese química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Tetra-Hidronaftalenos/síntese química , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Disponibilidade Biológica , Cristalografia por Raios X , Desenho de Fármacos , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/enzimologia , Melanoma Experimental/patologia , Camundongos , Camundongos Nus , Modelos Moleculares , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Estereoisomerismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Our continued effort toward the development of the imidazo[1,2-a]pyrazine scaffold as Aurora kinase inhibitors is described. Bioisosteric approach was applied to optimize the 8-position of the core. Several new potent Aurora A/B dual inhibitors, such as 25k and 25l, were identified.
Assuntos
Imidazóis/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/química , Animais , Aurora Quinase A , Aurora Quinases , Avaliação Pré-Clínica de Medicamentos , Imidazóis/síntese química , Imidazóis/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Pirazinas/síntese química , Pirazinas/farmacocinética , RatosRESUMO
The discovery of novel pyrazoline derivatives as B-Raf (V600E) inhibitors is described in this report. Chemical modification of the pyrazoline scaffold led to the development of SAR and identified potent and selective inhibitors of B-Raf (V600E). Determination of the pharmacokinetic properties of selected inhibitors is also reported.
Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/química , Substituição de Aminoácidos , Sítios de Ligação , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirazóis/síntese química , Pirazóis/farmacocinética , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
A high throughput screen identified N-aroylpyrazoline 1 as a selective inhibitor of the V600E mutant of B-Raf kinase. Parallel synthesis of acyl, aroyl, and sulfonyl derivatives led to the identification of several potent inhibitors in both enzymatic and cellular (pERK) assays such as compound 42.
Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/química , Piridinas/química , Substituição de Aminoácidos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
Recently, significant attention has been focused on the synthesis small-molecule libraries based on natural product or natural product-like structures. In this paper, we report our initial studies on the use of the 1,7-dioxaspiro[5,5]undecane (spiroketal) moiety as a rigid-core template for elaboration using parallel synthesis techniques. The synthesis of a spiroketal scaffold that is reminiscent of the spiroketal subunits found in the spiroketal macrolide antibiotics will be described. Elaboration of three independently addressable functional groups on the scaffold using solution-phase parallel synthesis techniques led to the preparation of a small library of natural product-like compounds. These studies pave the way for evaluation of highly functionalized spiroketals in phenotypic assays and as prospective antagonists of protein-protein interactions.