RESUMEN
Bruton's tyrosine kinase (BTK) is a promising drug target for the treatment of multiple diseases, such as B-cell malignances, asthma, and rheumatoid arthritis. A series of novel aminotriazines were identified as highly selective inhibitors of BTK by a scaffold-hopping approach. Subsequent SAR studies of this series using two conformationally different BTK proteins, an activated form of BTK and an unactivated form of BTK, led to the discovery of a highly selective BTK inhibitor, 4b. With significant efficacy in models in vivo and good ADME and safety profiles, 4b was advanced into preclinical studies.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Artritis Experimental/prevención & control , Diseño de Fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antituberculosos/síntesis química , Antituberculosos/farmacología , Artritis Experimental/inducido químicamente , Artritis Experimental/microbiología , Artritis Reumatoide/microbiología , Artritis Reumatoide/prevención & control , Masculino , Ratones , Ratones Endogámicos DBA , Estructura Molecular , Tuberculosis/complicaciones , Tuberculosis/microbiologíaRESUMEN
Fragment-based lead discovery is a new approach for lead generation that has emerged in the past decade. Because the initial fragments identified in the fragment screening typically show weak binding affinity, an intensive medicinal chemistry effort would be required to grow initial fragments into a potential lead compound. Here we demonstrate a kinase focused evolved fragment (KFEF) library, constructed by click chemistry-based fragment assembly, that is a valuable source of kinase inhibitors. This combinatorial assembly of two fragments, kinase-privileged alkyne fragments and diversified azide fragments, by two cycloaddition reactions shows a unique potential for the one-step synthesis of structurally diverse evolved fragments. The screening of this triazole-based KFEF library allowed the rapid identification of potent lead candidates for FLT3 and GSK3ß kinase.
Asunto(s)
Química Farmacéutica/métodos , Química Clic/métodos , Adenosina Trifosfato/química , Técnicas Químicas Combinatorias , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/farmacología , Perfilación de la Expresión Génica , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Triazoles/química , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
A series of tryptamine-based 2-thiophenesulfonamide derivatives were prepared and their agonistic activity for the beta-adrenergic receptors (ARs) was evaluated. Compound 54, containing 7-methanesulfonyloxy tryptamine, was found to be a highly potent beta3-AR agonist (EC50=0.21 nM, IA=97%) with excellent selectivity for the beta3-AR over the beta1- and beta2-ARs (210- and 86-fold, respectively).
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/síntesis química , Indoles/química , Triptaminas/química , Agonistas de Receptores Adrenérgicos beta 1 , Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/química , Evaluación Preclínica de Medicamentos , Humanos , Conformación Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
A series of tryptamine derivatives with modified sulfonamide were designed, synthesized, and evaluated for their ability to stimulate cAMP accumulation in CHO cells expressing the cloned human beta3-adrenergic receptor (AR). For this series of compounds, our objective was to symmetrize the alpha-position of the tryptamine moiety maintaining its activity and reducing the cost of production. Compound 11h, having m-aminobenzene, exhibited excellent agonistic activity for beta3-AR with excellent subtype selectivity.