RESUMEN
B-cell lymphoma 6 (BCL6) is a zinc finger transcriptional repressor possessing a BTB-POZ (BR-C, ttk, and bab for BTB; pox virus and zinc finger for POZ) domain, which is required for homodimerization and association with corepressors. BCL6 has multiple roles in normal immunity, autoimmunity, and some types of lymphoma. Mice bearing disrupted BCL6 loci demonstrate suppressed high-affinity antibody responses to T-dependent antigens. The corepressor binding groove in the BTB-POZ domain is a potential target for small compound-mediated therapy. Several inhibitors targeting this binding groove have been described, but these compounds have limited or absent in vivo activity. Biophysical studies of a novel compound, GSK137, showed an in vitro pIC50 of 8 and a cellular pIC50 of 7.3 for blocking binding of a peptide derived from the corepressor silencing mediator for retinoid or thyroid hormone receptors to the BCL6 BTB-POZ domain. The compound has good solubility (128 µg/ml) and permeability (86 nM/s). GSK137 caused little change in cell viability or proliferation in four BCL6-expressing B-cell lymphoma lines, although there was modest dose-dependent accumulation of G1 phase cells. Pharmacokinetic studies in mice showed a profile compatible with achieving good levels of target engagement. GSK137, administered orally, suppressed immunoglobulin G responses and reduced numbers of germinal centers and germinal center B cells following immunization of mice with the hapten trinitrophenol. Overall, we report a novel small-molecule BCL6 inhibitor with in vivo activity that inhibits the T-dependent antigen immune response.
Asunto(s)
Proteínas Proto-Oncogénicas c-bcl-6 , Animales , Linfocitos B/metabolismo , Humanos , Ratones , Transcripción Genética , Dedos de ZincRESUMEN
The peptide hormone human relaxin-2 (H2-RLX) has emerged as a potential therapy for cardiovascular and fibrotic diseases, but its short in vivo half-life is an obstacle to long-term administration. The discovery of ML290 demonstrated that it is possible to identify small molecule agonists of the cognate G-protein coupled receptor for H2-RLX (relaxin family peptide receptor-1 (RXFP1)). In our efforts to generate a new medicine for liver fibrosis, we sought to identify improved small molecule functional mimetics of H2-RLX with selective, full agonist or positive allosteric modulator activity against RXFP1. First, we confirmed expression of RXFP1 in human diseased liver. We developed a robust cellular cAMP reporter assay of RXFP1 signaling in HEK293 cells transiently expressing RXFP1. A high-throughput screen did not identify further specific agonists or positive allosteric modulators of RXFP1, affirming the low druggability of this receptor. As an alternative approach, we generated novel ML290 analogues and tested their activity in the HEK293-RXFP1 cAMP assay and the human hepatic cell line LX-2. Differences in activity of compounds on cAMP activation compared with changes in expression of fibrotic markers indicate the need to better understand cell- and tissue-specific signaling mechanisms and their disease-relevant phenotypes in order to enable drug discovery.
Asunto(s)
Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos/métodos , Activadores de Enzimas/aislamiento & purificación , Cirrosis Hepática/tratamiento farmacológico , Receptores Acoplados a Proteínas G/agonistas , Receptores de Péptidos/agonistas , Biopsia , Células Cultivadas , Activadores de Enzimas/síntesis química , Activadores de Enzimas/farmacología , Ensayos Analíticos de Alto Rendimiento , Humanos , Cirrosis Hepática/patologíaRESUMEN
This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimer's disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties.
Asunto(s)
Benzazepinas/química , Antagonistas de los Receptores Histamínicos H3/química , Receptores Histamínicos H3/química , Animales , Benzazepinas/farmacocinética , Perros , Semivida , Haplorrinos , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Niacinamida/análogos & derivados , Niacinamida/química , Niacinamida/farmacocinética , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores Histamínicos H3/metabolismo , Relación Estructura-ActividadRESUMEN
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.
Asunto(s)
Benzazepinas/química , Antagonistas de los Receptores Histamínicos H3/química , Receptores Histamínicos H3/química , Animales , Benzazepinas/síntesis química , Benzazepinas/farmacocinética , Citocromo P-450 CYP2D6/química , Citocromo P-450 CYP2D6/metabolismo , Evaluación Preclínica de Medicamentos , Semivida , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Unión Proteica , Ratas , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relación Estructura-ActividadRESUMEN
Acid pump antagonists (APAs) such as the imidazo[1,2-a]pyridine AZD-0865 2 have proven efficacious at low oral doses in acid related gastric disorders. Herein we describe some of the broader SAR in this class of molecule and detail the discovery of an imidazo[1,2-a]pyridine 15 which has excellent efficacy in animal models of gastric acid secretion following oral administration, as well as a good overall developability profile. The discovery strategy focuses on use of heteroaryl and heterocyclic substituents at the C-6 position and optimization of developability characteristics through modulation of global physico-chemical properties.
Asunto(s)
Inhibidores de la Bomba de Protones , Inhibidores de la Bomba de Protones/química , Piridinas/química , Administración Oral , Animales , Perros , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Inhibidores de la Bomba de Protones/síntesis química , Inhibidores de la Bomba de Protones/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Modification of the potent imidazole-based B-Raf inhibitor SB-590885 resulted in the identification of a series of furan-based derivatives with enhanced CNS penetration. One such compound, SB-699393 (17), was examined in vivo to challenge the hypothesis that selective B-Raf inhibitors may be of value in the treatment of stroke.
Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Furanos/síntesis química , Furanos/farmacología , Indanos/síntesis química , Indanos/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Animales , Furanos/química , Imidazoles/química , Imidazoles/farmacología , Indanos/química , Estructura Molecular , Piridinas/química , Piridinas/farmacología , Ratas , Accidente Cerebrovascular/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
The biphenyl amides (BPAs) are a series of p38alpha MAP kinase inhibitors. Compounds are able to bind to the kinase in either the DFG-in or DFG-out conformation, depending on substituents. X-ray, binding, kinetic and cellular data are shown, providing the most detailed comparison to date between potent compounds from the same chemical series that bind to different p38alpha conformations. DFG-out-binding compounds could be made more potent than DFG-in-binding compounds by increasing their size. Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Amidas/sangre , Amidas/química , Aminoácidos/genética , Aminoácidos/metabolismo , Sitios de Unión , Compuestos de Bifenilo/sangre , Compuestos de Bifenilo/química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Diseño de Fármacos , Lipopolisacáridos/farmacología , Conformación Molecular , Estructura Molecular , Naftalenos/farmacología , Pirazoles/farmacología , Relación Estructura-ActividadRESUMEN
A series of ketopiperazines were prepared and evaluated for their activity as histamine H 3 antagonists. From investigation of the tertiary basic center in the aminopropyloxyphenyl template, the 2( R)-methylpyrrolidine was identified as the most potent amine. In the more rigid piperidineoxyphenyl template the N-cyclobutyl group was the most potent amine. The 4-fluorobenzyol, 4-cyanobenzoyl, and 2,4-difluorobenzoyl groups provided good pharmacokinetic profiles for the various amides. The PSA and log D values of these compounds suggested low brain penetration. The compounds had very high selectivity over other receptors and did not inhibit hepatic cytochrome P450, indicating low drug-drug interaction potential. Compound 22i was identified as the best compound of this series based on its overall profile of high potency, selectivity, low brain penetration, lack of CYP450 inhibition, high oral bioavailability, and pharmacokinetic properties.
Asunto(s)
Encéfalo/metabolismo , Antagonistas de los Receptores Histamínicos H3/síntesis química , Piperazinas/síntesis química , Administración Oral , Animales , Barrera Hematoencefálica/metabolismo , Células CHO , Corteza Cerebral/metabolismo , Cricetinae , Cricetulus , Sistema Enzimático del Citocromo P-450/metabolismo , Perros , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Cobayas , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Antagonistas de los Receptores Histamínicos H3/farmacología , Humanos , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Isoenzimas/metabolismo , Contracción Isométrica/efectos de los fármacos , Masculino , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Piperazinas/farmacocinética , Piperazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
This paper reports a study into the partial reduction of N-alkylpyridinium salts together with subsequent elaboration of the intermediates thus produced. Activation of a pyridinium salt by placing an ester group at C-2, allows the addition of two electrons to give a synthetically versatile enolate intermediate which can be trapped with a variety of electrophiles. Furthermore, the presence of a 4-methoxy substituent on the pyridine nucleus enhances the stability of the enolate reaction products, and hydrolysis in situ gives stable dihydropyridone derivatives in good yields. These versatile compounds are prepared in just three steps from picolinic acid and can be derivatised at any position on the ring, including nitrogen when a p-methoxybenzyl group is used as the N-activating group on the pyridinium salt. This publication describes our exploration of the optimum reducing conditions, the most appropriate N-alkyl protecting group, as well as the best position on the ring for the methoxy group. Electrochemical techniques which mimic the synthetic reducing conditions are utilised and they give clear support for our proposed mechanism of reduction in which there is a stepwise addition of two electrons to the heterocycle, mediated by di-tert-butylbiphenyl (DBB). Moreover, there is a correlation between the viability of reduction of a given heterocycle under synthetic conditions and its electrochemical response; this offers the potential for use of electrochemistry in predicting the outcome of such reactions.
Asunto(s)
Amoníaco , Compuestos de Piridinio/química , Compuestos de Bifenilo/síntesis química , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular , Oxidación-Reducción , Compuestos de Piridinio/síntesis química , Piridonas/síntesis químicaRESUMEN
The novel imidazo[4,5-c]pyridine 1,2,5-oxadiazol-3-yl template affords an excellent start point for identification of inhibitors of a number of protein kinases. Here we report on its optimisation for mitogen and stress-activated protein kinase-1 (MSK-1) inhibitory activity, and selectivity over other kinases.
Asunto(s)
Aminas/farmacología , Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Oxadiazoles/farmacología , Piridinas/farmacología , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Aminas/síntesis química , Aminas/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Imidazoles/síntesis química , Imidazoles/química , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Piridinas/síntesis química , Piridinas/química , Relación Estructura-ActividadRESUMEN
A novel series of imidazo[4,5-c]pyridines bearing a 1,2,5-oxadiazol-3-ylamine functionality has been developed. These are potent inhibitors of mitogen and stress-activated protein kinase-1.
Asunto(s)
Aminas/farmacología , Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Oxadiazoles/farmacología , Piridinas/farmacología , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Aminas/síntesis química , Aminas/clasificación , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/clasificación , Imidazoles/síntesis química , Imidazoles/clasificación , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/clasificación , Piridinas/síntesis química , Piridinas/clasificación , Relación Estructura-ActividadRESUMEN
[reaction: see text] The addition of two electrons to a pyridinium salt turns it into a nucleophile. The intermediate generated by the reduction of such salts can be reacted successfully with a range of different electrophiles (acids, alkyl halides, and carbonyl compounds) and the intermediate hydrolyzed in situ to provide a wide range of dihydropyridones. Each position on the dihydropyridone ring is then accessible using standard synthetic manipulations.