RESUMEN
Progress in the identification of suitable RORγ inverse agonists as clinical candidates has been hampered by the high lipophilicity that seems required for high potency on this nuclear receptor. In this context, we decided to focus on the replacement of the hydroxymethyl group found on known modulators to determine if more polarity could be tolerated in this position. SAR of the replacement of this moiety is presented in this article leading to the identification of sulfoximine derivatives as potent modulators with pharmacological activity in the in vivo mouse Imiquimod psoriasis model.
Asunto(s)
Iminas/farmacología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Sulfonamidas/farmacología , Sulfóxidos/farmacología , Animales , Agonismo Inverso de Drogas , Femenino , Humanos , Iminas/síntesis química , Iminas/química , Ligandos , Ratones Endogámicos BALB C , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfóxidos/síntesis química , Sulfóxidos/químicaRESUMEN
With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with inâ vivo activity in an IL-23-induced mouse skin inflammation model.
Asunto(s)
Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Psoriasis/tratamiento farmacológico , Sulfonamidas/química , Administración Tópica , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Agonismo Inverso de Drogas , Humanos , Concentración 50 Inhibidora , Interleucina-17/metabolismo , Interleucina-23/farmacología , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Ratones , Ratones Endogámicos BALB C , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Psoriasis/patología , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/tratamiento farmacológico , Enfermedades de la Piel/patología , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Sulfonamidas/uso terapéutico , Células Th17/citología , Células Th17/efectos de los fármacos , Células Th17/metabolismoRESUMEN
Targeting the TNFα pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a. Starting from hits plagued with poor solubility or genotoxicity, 26a was identified through thorough multiparameter optimisation. Showing robust in vivo activity in an oxazolone-mediated inflammation model, the compound was selected for development. Following a polymorph screen, the hydrochloride salt was selected and the synthesis was efficiently developed to yield the API in 47% overall yield.
Asunto(s)
Proteína ADAM17/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Proteína ADAM17/metabolismo , Administración Tópica , Animales , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Ácidos Hidroxámicos/química , Ratones , Ratones Pelados , Microsomas Hepáticos/metabolismo , Oxazolona/toxicidad , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/prevención & control , Enfermedades de la Piel/veterinaria , Solubilidad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Rosacea is a common skin disease with a high impact on quality of life. Characterized by erythema, edema, burning pain, immune infiltration, and facial skin fibrosis, rosacea has all the characteristics of neurogenic inflammation, a condition induced by sensory nerves via antidromically released neuromediators. To investigate the hypothesis of a central role of neural interactions in the pathophysiology, we analyzed molecular and morphological characteristics in the different subtypes of rosacea by immunohistochemistry, double immunofluorescence, morphometry, real-time PCR, and gene array analysis, and compared the findings with those for lupus erythematosus or healthy skin. Our results showed significantly dilated blood and lymphatic vessels. Signs of angiogenesis were only evident in phymatous rosacea. The number of mast cells and fibroblasts was increased in rosacea, already in subtypes in which fibrosis is not clinically apparent, indicating early activation. Sensory nerves were closely associated with blood vessels and mast cells, and were increased in erythematous rosacea. Gene array studies and qRT-PCR confirmed upregulation of genes involved in vasoregulation and neurogenic inflammation. Thus, dysregulation of mediators and receptors implicated in neurovascular and neuroimmune communication may be crucial at early stages of rosacea. Drugs that function on neurovascular and/or neuroimmune communication may be beneficial for the treatment of rosacea.
Asunto(s)
Inflamación Neurogénica/inmunología , Inflamación Neurogénica/fisiopatología , Rosácea/inmunología , Rosácea/fisiopatología , Piel/inervación , Piel/fisiopatología , Fibroblastos/inmunología , Fibroblastos/fisiología , Perfilación de la Expresión Génica , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/fisiopatología , Vasos Linfáticos/inmunología , Vasos Linfáticos/fisiopatología , Mastocitos/inmunología , Mastocitos/fisiología , Neovascularización Patológica/genética , Neovascularización Patológica/inmunología , Neovascularización Patológica/fisiopatología , Inflamación Neurogénica/genética , Inflamación Neurogénica/patología , Rosácea/genética , Rosácea/patología , Piel/irrigación sanguínea , Piel/patología , Regulación hacia Arriba , Vasodilatación/genética , Vasodilatación/inmunología , Vasodilatación/fisiología , Vimentina/análisis , Vimentina/inmunologíaRESUMEN
BACKGROUND: Epidermal homeostasis involves the monitoring of continuous proliferative and differentiative processes as keratinocytes migrate from the basal layer to the skin surface. Recently, differentiation of epidermal stem cells was shown to be promoted by the Notch pathway. This pathway is characterised by cell-cell interactions between transmembrane proteins and was first implicated in lateral inhibition, patterning and cell binary choices during embryogenesis. METHODS: By in situ hybridisation, we investigated the in vivo expression of related genes, namely; Notch 1-3, Delta 1, Jagged 1, Lunatic Fringe, Radical Fringe and Manic Fringe during keratinocyte proliferation and differentiation in humans in basal cell carcinoma, psoriasis and in wound healing experiments, compared with normal adult skin. RESULTS: We show that the highest level of transcription of these genes is in the basal cell layer of non-lesional skin. Conversely, when keratinocytes were hyperproliferating, as in basal cell carcinoma, psoriasis, and during the first step of re-epithelialisation, expression was weak or non-existent. Furthermore, normal levels of transcripts were rescued in psoriatic plaques when treated by phototherapy, as well as in newly regenerated stratified epidermis following wound healing. CONCLUSION: The Notch signalling involved in the differentiation programme of normal adult human epidermis is altered under experimental conditions and pathologies which modify this programme.