RESUMEN
High-throughput screening identified compound 1 as a potent P2X(7) receptor antagonist suitable for lead optimisation. Structure-activity relationships (SAR) of a series of (1H-pyrazol-4-yl)acetamides were investigated and compound 32 was identified as a potent P2X(7) antagonist with enhanced potency and favourable physicochemical and pharmacokinetic properties.
Asunto(s)
Acetamidas/química , Antiinfecciosos/síntesis química , Antagonistas del Receptor Purinérgico P2 , Pirazoles/síntesis química , Acetamidas/síntesis química , Acetamidas/farmacocinética , Administración Oral , Animales , Antiinfecciosos/química , Antiinfecciosos/farmacocinética , Ensayos Analíticos de Alto Rendimiento , Humanos , Inyecciones Intravenosas , Pirazoles/química , Pirazoles/farmacocinética , Ratas , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X7 , Relación Estructura-ActividadRESUMEN
The identification of novel, potent, non-steroidal/small molecule functional GR antagonist GSK1564023A selective over PR is described. Associated structure-activity relationships and the process of optimisation of an initial HTS hit are also described.
Asunto(s)
Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Ratas , Bibliotecas de Moléculas Pequeñas/metabolismo , Relación Estructura-ActividadRESUMEN
In the course of optimizing a novel indazole sulfonamide series that inhibits ß-ketoacyl-ACP synthase (KasA) of Mycobacterium tuberculosis, a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts.
Asunto(s)
3-Oxoacil-(Proteína Transportadora de Acil) Sintasa/antagonistas & inhibidores , Compuestos de Anilina/farmacología , Mycobacterium tuberculosis , Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Sitios de Unión , Daño del ADN , Mycobacterium tuberculosis/enzimologíaRESUMEN
The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.
Asunto(s)
Ensayos Analíticos de Alto Rendimiento/métodos , Proteínas/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Quimiocina CCL2/biosíntesis , Cristalografía por Rayos X , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Humanos , Interleucina-6/antagonistas & inhibidores , Leucocitos/efectos de los fármacos , Masculino , Ratones , Modelos Moleculares , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Bibliotecas de Moléculas PequeñasRESUMEN
A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent small molecule agonists of the human TGR5 G-protein coupled receptor is described. Subsequent optimization resulted in the rapid identification of potent exemplars 6 and 7 which demonstrated improved GLP-1 secretion in vivo via an intracolonic dose coadministered with glucose challenge in a canine model. These novel TGR5 receptor agonists are potentially useful therapeutics for metabolic disorders such as type II diabetes and its associated complications.