RESUMEN
We have previously reported the syntheses of a series of 3,6-disubstituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). These molecules are potent binders but are high molecular weight and they exhibited poor solubility at pH 2 and pH 7. This manuscript details our efforts at improving physical chemical properties for this series of compounds by increasing the diversity at the 3-position (i.e. introducing heteroatoms and lowering the molecular weight). These efforts have led to molecules which are potent binders with improved solubility.
Asunto(s)
Agonismo Inverso de Drogas , Quinolinas/agonistas , Animales , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A high-throughput screen of the ligand binding domain of the nuclear receptor retinoic acid-related orphan receptor gamma t (RORγt) employing a thermal shift assay yielded a quinoline tertiary alcohol hit. Optimization of the 2-, 3- and 4-positions of the quinoline core using structure-activity relationships and structure-based drug design methods led to the discovery of a series of modulators with improved RORγt inhibitory potency and inverse agonism properties.
Asunto(s)
Diseño de Fármacos , Agonismo Inverso de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Quinolinas/química , Quinolinas/farmacología , Humanos , Simulación del Acoplamiento Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Relación Estructura-Actividad , Células Th17/efectos de los fármacosRESUMEN
We identified 6-substituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). The synthesis of this class of RORγt modulators is reported, and optimization of the substituents at the quinoline 6-position that produced compounds with high affinity for the receptor is detailed. This effort identified molecules that act as potent, full inverse agonists in a RORγt-driven cell-based reporter assay. The X-ray crystal structures of two full inverse agonists from this chemical series bound to the RORγt ligand binding domain are disclosed, and we highlight the interaction of a hydrogen-bond acceptor on the 6-position substituent of the inverse agonist with Glu379:NH as a conserved binding contact.
Asunto(s)
Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Quinolinas/farmacología , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
B-RAF mutations have been identified in the majority of melanoma and a large fraction of colorectal and papillary thyroid carcinoma. Drug discovery efforts targeting mutated B-RAF have yielded several interesting molecules, and currently, three compounds are undergoing clinical evaluation. Inhibition of B-RAF in animal models leads to a slowing of tumor growth and, in some cases, tumor reduction. Described within is a novel series of diaryl imidazoles with potent, single-digit nanomolar, anti-B-RAF activity. One compound from this series has been detailed here and has been shown to block B-RAF(V600E)-dependent extracellular signal-regulated kinase 1/2 phosphorylation in SK-MEL-28 melanoma cells as well as soft agar colony formation and proliferation. Importantly, interleukin-8 (IL-8) was identified by quantitative real-time PCR and ELISA as a product of the elevated mitogen-activated protein kinase signaling in these cells. Plasma concentrations of IL-8 in mice bearing melanoma xenografts were significantly reduced following exposure to B-RAF inhibitors. Taken together, these data suggest that IL-8 could serve as a tractable clinical biomarker.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Interleucina-8/antagonistas & inhibidores , Melanoma/metabolismo , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Humanos , Imidazoles/farmacología , Interleucina-8/biosíntesis , Interleucina-8/genética , Melanoma/patología , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/genética , Trasplante HeterólogoRESUMEN
Computer aided modeling guided the design of a series of diarylimidazole compounds (11-22) intended to interact with both the ATP and adjacent allosteric binding domains of B-RAF kinase. Their ability to inhibit the function of B-RAF kinase and intracellular ERK1/2 phosphorylation were evaluated.
Asunto(s)
Diseño Asistido por Computadora , Hidrocarburos Aromáticos/farmacología , Imidazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Adenosina Trifosfato/metabolismo , Sitio Alostérico , Cristalografía por Rayos X , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Hidrocarburos Aromáticos/síntesis química , Imidazoles/síntesis química , Concentración 50 Inhibidora , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Relación Estructura-ActividadRESUMEN
This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects.
Asunto(s)
Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Animales , Artritis/inducido químicamente , Artritis/prevención & control , Colágeno , Perros , Diseño de Fármacos , Descubrimiento de Drogas , Histamina , Indicadores y Reactivos , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Modelos Moleculares , Prurito/inducido químicamente , Prurito/prevención & control , Ratas , Ratas Sprague-Dawley , Receptores Histamínicos , Receptores Histamínicos H4 , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
The synthesis and structure-activity relationships of a series of novel phenoxyphenyl diamine derivatives with affinity for both the histamine H(3) receptor and the serotonin transporter is described.
Asunto(s)
Diaminas/química , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H3/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Antagonistas de los Receptores Histamínicos/síntesis química , Humanos , Estructura Molecular , Receptores Histamínicos H3/química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Relación Estructura-ActividadRESUMEN
Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified.
Asunto(s)
Química Farmacéutica/métodos , Receptor Cannabinoide CB2/química , Sulfonas/química , Animales , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Cinética , Ligandos , Modelos Químicos , Unión Proteica , Ratas , Receptores de Droga , Sodio/química , Relación Estructura-ActividadRESUMEN
A series of novel and potent pyrrolidino-tetrahydroisoquinolines with dual histamine H(3) antagonist/serotonin transporter inhibitor activity is described. A highly regio- and diastereoselective synthesis of the pyrrolidino-tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH(3) was developed. In vitro and in vivo data are discussed.
Asunto(s)
Química Farmacéutica/métodos , Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H3/química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Serotonina/química , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/farmacología , Animales , Depresión/tratamiento farmacológico , Diseño de Fármacos , Humanos , Cinética , Modelos Químicos , Conformación Molecular , RatasRESUMEN
In an attempt to search for a new class of antibacterial agents, we have discovered a series of pyrazole analogs that possess good antibacterial activity for Gram-positive and Gram-negative organisms via inhibition of type II bacterial topoisomerases. We have investigated the structure-activity relationships of this series, with an emphasis on the length and conformation of the linker. This work led to the identification of tetrahydroindazole analogs, such as compound 1, as the most potent class of compounds.
Asunto(s)
Antibacterianos/síntesis química , Inhibidores Enzimáticos/síntesis química , Pirazoles/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Diseño de Fármacos , Resistencia a Múltiples Medicamentos/fisiología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirazoles/química , Pirazoles/farmacología , Relación Estructura-Actividad , Inhibidores de Topoisomerasa IIRESUMEN
Bacterial elongation factor Tu (EF-Tu) and EF-Ts are interacting proteins involved in polypeptide chain elongation in protein biosynthesis. A novel scintillation proximity assay for the detection of inhibitors of EF-Tu and EF-Ts, as well as the interaction between them, was developed and used in a high-throughput screen of a chemical library. Several compounds from a variety of chemical series with inhibitory properties were identified, including certain indole dipeptides, benzimidazole amidines, 2-arylbenzimidazoles, N-substituted imidazoles, and N-substituted guanidines. The in vitro activities of these compounds were confirmed in a coupled bacterial transcription-translation assay. Several indole dipeptides were identified as inhibitors of bacterial translation, with compound 2 exhibiting a 50% inhibitory concentration of 14 microM and an MIC for S. aureus ATCC 29213 of 5.6 microg/ml. Structure-activity relationship studies around the dipeptidic indoles generated additional analogs with low micromolar MICs for both gram-negative and gram-positive bacteria. To assess the specificity of antibacterial action, these compounds were evaluated in a metabolic labeling assay with Staphylococcus aureus. Inhibition of translation, as well as limited effects on other macromolecular pathways for some of the analogs studied, indicated a possible contribution from a non-target-based antibacterial mechanism of action.
Asunto(s)
Antibacterianos/química , Dipéptidos/química , Dipéptidos/farmacología , Indoles/química , Factor Tu de Elongación Peptídica/antagonistas & inhibidores , Factores de Elongación de Péptidos/antagonistas & inhibidores , Antibacterianos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Cocos Grampositivos/efectos de los fármacos , Guanidinas/química , Guanidinas/farmacología , Imidazoles/química , Imidazoles/farmacología , Sustancias Macromoleculares/metabolismo , Pruebas de Sensibilidad Microbiana , Factor Tu de Elongación Peptídica/metabolismo , Factores de Elongación de Péptidos/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Relación Estructura-Actividad , Transcripción Genética/efectos de los fármacosRESUMEN
We recently reported that compound 1 is a potent inhibitor of the CB2 receptor with high selectivity over CB1. This paper describes the SAR development for this class of compounds. Variation of the substitution pattern on the aromatic rings, as well as the groups linking them together, led to sub-nanomolar inhibitors of the CB2 receptor, with high selectivity over CB1.
Asunto(s)
Receptor Cannabinoide CB2/metabolismo , Sulfonas/metabolismo , Ligandos , Receptor Cannabinoide CB2/antagonistas & inhibidores , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
A series of benzoylpiperidine analogs related to 4a was prepared, and their ability to inhibit the uptake of [(14)C]-glycine in COS7 cells transfected with human glycine transporter type-2 (GlyT-2) was evaluated. Small structural changes to the benzoylpiperidine region of the molecule led to a significant decrease in GlyT-2 inhibitory activity. In contrast, the distal aryl ring was more tolerant to functional group modifications and could accommodate a variety of substitutes at the C-2 or C-3 positions. Comparable activities to 4a were obtained by replacing the anilino nitrogen with an ether linkage 27 or by exchanging the isopropoxy ether moiety with an isopropyl amino group 15. A distinct preference for a 2-carbon tether (n=1) was observed relative to the corresponding 3-carbon homolog (n=2).
Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inhibidores , Benzoatos/química , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Sistemas de Transporte de Aminoácidos Neutros/genética , Animales , Transporte Biológico/efectos de los fármacos , Células COS , Chlorocebus aethiops , Glicina/metabolismo , Proteínas de Transporte de Glicina en la Membrana Plasmática , Inhibidores de la Captación de Neurotransmisores/química , Piperidinas/químicaRESUMEN
A variety of alpha-amino acid derivatives were prepared as glycine transport inhibitors and their ability to block the uptake of [(14)C]-glycine in COS7 cells transfected with human glycine transporter-2 (hGlyT-2) was evaluated. An array of substituents at the chiral center was studied and overall, L-phenylalanine was identified as the preferred amino acid residue. Compounds prepared from l-amino acids were more potent GlyT-2 inhibitors than analogs derived from the corresponding d-amino acids. Introducing an achiral amino acid such as glycine, or incorporating geminal substitution in the alpha-position, led to a significant reduction in GlyT-2 inhibitory properties.
Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inhibidores , Aminoácidos/química , Aminoácidos/farmacología , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Sistemas de Transporte de Aminoácidos Neutros/genética , Aminoácidos/síntesis química , Animales , Transporte Biológico/efectos de los fármacos , Células COS , Chlorocebus aethiops , Glicina/metabolismo , Proteínas de Transporte de Glicina en la Membrana Plasmática , Inhibidores de la Captación de Neurotransmisores/síntesis química , Fenilalanina/análogos & derivados , Fenilalanina/farmacologíaRESUMEN
Several beta- and gamma-amino acid derivatives were prepared as glycine transport inhibitors and their ability to block the uptake of [(14)C]-glycine in COS7 cells transfected with human glycine transporter-2 (hGlyT-2) were evaluated. A range of lipophilic side chains were tolerated in the beta-amino acid series (i.e., Ph, CH(2)Ph, CH(CH(3))(2), and CH(2)CH(CH(3))(2)). In the gamma-amino acid series, minimal differences in potency were observed between the alpha,beta-unsaturated analogs and the corresponding saturated derivatives. In both series, a 4-biphenyl or 4-phenoxyphenyl substituent appended to the urea or cyanogunaidine moiety was necessary for in vitro activity.