RESUMEN
In our hands, efficient access to the 4-amino-3-carboxamide disubstituted pyridine-2(1H)-one kinase hinge-binder motif proved to be more challenging than anticipated requiring a significant investment in route scouting and optimization. This full paper focuses on the synthesis issues that we encountered during our route exploration and the original solutions we found that helped us to identify two optimized library-style processes to prepare our large kinase inhibitor library.
RESUMEN
Retinoids have a dominant role in topical acne therapy and to date, only RARß and RARγ dual agonists have reached the market. Given the tissue distribution of RAR isoforms, it was hypothesized that developing RARγ -selective agonists could yield a new generation of topical acne treatments that would increase safety margins while maintaining the robust efficacy of previous drugs. Structural knowledge derived from the X-ray structure of known γ-selective CD437, suggested the design of a novel triaryl series of agonists which was optimized and ultimately led to the discovery of Trifarotene/CD5789.
Asunto(s)
Acné Vulgar/tratamiento farmacológico , Diseño de Fármacos , Receptores de Ácido Retinoico/agonistas , Retinoides/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Retinoides/síntesis química , Retinoides/química , Relación Estructura-Actividad , Receptor de Ácido Retinoico gammaRESUMEN
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 IL17 pathway and more specifically the nuclear receptor RORγ is thought to be beneficial in multiple skin disorders. The Letter describes the discovery of phenoxyindazoles and thiophenoxy indazoles as potent RORγ inverse agonists. Optimization of the potency and efforts to mitigate the phototoxic liability of the series are presented. Finally, crystallization of the lead compound revealed that the series bound to an allosteric site of the nuclear receptor. Such compounds could be useful as tool compounds for understanding the impact of topical treatment on skin disease models.
Asunto(s)
Indazoles/química , Indazoles/farmacología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Agonismo Inverso de Drogas , Humanos , Simulación del Acoplamiento Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Relación Estructura-ActividadRESUMEN
Quer estimular o leitor a privilegiar uma atitude reflexiva em relação ao conhecimento médico, adotando uma perspectiva crítica, não meramente histórica, mas igualmente epistemológica. Apanhado cronológico com relatos sobre as conquistas determinantes da Medicina, a evolução de suas grandes opções teóricas e de suas metodologias de investigação. Através de quatro estudos de caso se apresentam e cruzam instrumentos de análise histórica, da filosofia e da sociologia das ciências, a fim de mostrar o entrelaçamento das lógicas inerentes aos procedimentos adotados por médicos e pesquisadores no decorrer dos séculos.