RESUMEN
A novel series of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as RORγt inverse agonists was discovered. Binding mode analysis of a RORγt partial agonist (2c) revealed by co-crystal structure in RORγt LBD suggests that the inverse agonists do not directly interfere with the interaction between H12 and the RORγt LBD. Detailed SAR exploration led to identification of potent RORγt inverse agonists such as 3m with a pIC50 of 8.0. Selected compounds in the series showed reasonable activity in Th17 cell differentiation assay as well as low intrinsic clearance in mouse liver microsomes.
Asunto(s)
Amidas/química , Amidas/farmacología , Agonismo Inverso de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Células Th17/efectos de los fármacos , Tiazoles/química , Tiazoles/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Humanos , Ratones , Simulación del Acoplamiento Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Células Th17/citologíaRESUMEN
2-Aminopyrimidin-4(1H)-one was proposed as the novel bioisostere of urea. Bioisosteric replacement of the reported urea series of the CXCR2 antagonists with 2-aminopyrimidin-4(1H)-ones led to the discovery of the novel and potent CXCR2 antagonist 3e. 2-Aminopyrimidin-4(1H)-one derivative 3e demonstrated a good developability profile (reasonable solubility and high permeability) and superior chemical stability especially in simulated gastric fluid (SGF) compared with ureas.
Asunto(s)
Pirimidinas/síntesis química , Receptores de Interleucina-8B/antagonistas & inhibidores , Urea/análogos & derivados , Humanos , Estructura Molecular , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
Novel series of N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides were discovered as potent retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitors. SAR studies of the RORγt HTS hit 6a led to identification of thiazole ketone amide 8h and thiophene ketone amide 9g with high binding affinity and inhibitory activity of Th17 cell differentiation. Compound 8h showed in vivo efficacy in both mouse experimental autoimmune encephalomyelitis (EAE) and collagen induced arthritis (CIA) models via oral administration.
Asunto(s)
Amidas/farmacología , Artritis/tratamiento farmacológico , Descubrimiento de Drogas , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Administración Oral , Amidas/administración & dosificación , Amidas/química , Animales , Artritis/inducido químicamente , Diferenciación Celular/efectos de los fármacos , Colágeno , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Relación Estructura-Actividad , Células Th17RESUMEN
We have discovered a novel complex crystal structure of the PHD2 enzyme with its inhibitor, the 2,8-diazaspiro[4.5]decan-1-one analogue 4b. The widely reported salt bridge between Arg383 of the enzyme and its inhibitors in all complex structures published thus far was not observed in our case. In our complex structure compound 4b forms several novel interactions with the enzyme, which include a hydrogen bond with Arg322, a π-cation interaction with Arg322, a π-π stacking with Trp389, and a π-π stacking with His313. Guided by the structural information, SAR studies were performed on the 2,8-diazaspiro[4.5]decan-1-one series leading to the discovery of compound 9p with high potency and good oral pharmacokinetic profile in mice.
Asunto(s)
Compuestos Aza/química , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Inhibidores de Prolil-Hidroxilasa/química , Piridinas/química , Administración Oral , Animales , Sitios de Unión , Cristalografía por Rayos X , Semivida , Humanos , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Inhibidores de Prolil-Hidroxilasa/síntesis química , Inhibidores de Prolil-Hidroxilasa/farmacocinética , Unión Proteica , Estructura Terciaria de Proteína , Piridinas/síntesis química , Piridinas/farmacocinética , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacocinética , Relación Estructura-ActividadRESUMEN
A novel series of benzoxazole-derived S1P(1) agonists were designed based on scaffold hopping molecular design strategy combined with computational approaches. Extensive SAR studies led to the discovery of compound 17d as a selective S1P(1) agonist (over S1P(3)) with high CNS penetration and favorable DMPK properties. 17d also demonstrated in vivo pharmacological efficacy to reduce blood lymphocyte in mice after oral administration.
Asunto(s)
Benzoxazoles/síntesis química , Inmunosupresores/síntesis química , Linfocitos/efectos de los fármacos , Receptores de Lisoesfingolípidos/agonistas , Administración Oral , Animales , Benzoxazoles/farmacología , Sitios de Unión , Calcio/metabolismo , Inmunosupresores/farmacología , Recuento de Linfocitos , Linfocitos/citología , Ratones , Modelos Moleculares , Unión Proteica , Receptores de Lisoesfingolípidos/metabolismo , Sensibilidad y Especificidad , Receptores de Esfingosina-1-Fosfato , Relación Estructura-ActividadRESUMEN
High-throughput screening of GSK compound collection led to the discovery of a novel series of thiadiazole amides as potent and S1P(3)-sparing sphingosine-1-phosphate 1 (S1P(1)) receptor agonists. Synthesis, structure and activity relationship, selectivity, and some developability properties are described.
Asunto(s)
Amidas/química , Factores Inmunológicos/química , Receptores de Lisoesfingolípidos/agonistas , Tiadiazoles/química , Amidas/farmacología , Animales , Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento , Humanos , Factores Inmunológicos/farmacología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Ratones , Receptores de Lisoesfingolípidos/química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad , Tiadiazoles/farmacologíaRESUMEN
Novel indole-propionic acid derivatives were developed as sphingosine-1-phosphate (S1P) receptor agonists through a systematic SAR study. The optimized and S1P(3) selective S1P(1) agonist 9f induced peripheral blood lymphocyte reduction in vivo and has an excellent efficacy in mouse experimental autoimmune encephalomyelitis (EAE).
Asunto(s)
Encefalomielitis Autoinmune Experimental , Indoles/química , Propionatos/química , Receptores de Lisoesfingolípidos/agonistas , Animales , Regulación hacia Abajo/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/terapia , Indoles/farmacología , Linfocitos/citología , Linfocitos/efectos de los fármacos , Ratones , Estructura Molecular , Propionatos/farmacología , Relación Estructura-ActividadRESUMEN
SAR of a novel series of pyridazine-derived γ-secretase modulators is described. Compound 25 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aß42 and Aß40, and maintain the levels of total Aß. Furthermore, 25 demonstrated excellent pharmacokinetic parameters as well as good CNS penetration in the rat.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Piridazinas/síntesis química , Péptidos beta-Amiloides/metabolismo , Animales , Supervivencia Celular , Células Cultivadas , Activación Enzimática/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Piridazinas/química , Piridazinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
SAR of a novel series of pyridine-derived γ-secretase modulators is described. Compound 5 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aß42 and Aß40, and maintain (or increase) the levels of total Aß. Furthermore, representative compounds 1 and 5 demonstrated in vivo efficacy to lower Aß42 in the brain without altering Notch processing in the peripheral.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Piridinas/farmacología , Animales , Disponibilidad Biológica , Inhibidores Enzimáticos del Citocromo P-450 , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Gene identification followed by determination of the expression of genes in a given disease and understanding of the function of the gene products is central to the drug discovery process. The ability to associate a specific gene with a disease can be attributed primarily to the extraordinary progress that has been made in the areas of gene sequencing and information technologies. Selection and validation of novel molecular targets have become of great importance in light of the abundance of new potential therapeutic drug targets that have emerged from human gene sequencing. In response to this revolution within the pharmaceutical industry, the development of high-throughput methods in both biology and chemistry has been necessitated. Further, the successful translation of basic scientific discoveries into clinical experimental medicine and novel therapeutics is an increasing challenge. As such, a new paradigm for drug discovery has emerged. This process involves the integration of clinical, genetic, genomic, and molecular phenotype data partnered with cheminformatics. Central to this process, the data generated are managed, collated, and interpreted with the use of informatics. This review addresses the use of new technologies that have arisen to deal with this new paradigm.
Asunto(s)
Diseño de Fármacos , Genoma Humano , Biotecnología , Industria Farmacéutica , Genómica , Humanos , Farmacogenética , ProteómicaRESUMEN
Structure-activity relationship exploration of the historical biarylurea series led to the identification of novel CNS penetrant CXCR2 antagonists with nanomolar potency, favorable PK profile, and good developability potentials. More importantly, the key compound 22 showed efficacy in a cuprizone-induced demyelination model with twice daily oral administration, thereby supporting CXCR2 to be a potential therapeutic target for the treatment of demyelinating diseases such as multiple sclerosis.
RESUMEN
A novel series of biaryl amides was identified as RORγt inhibitors through core replacement of a starting hit 1. Structure-activity relationship exploration on the biaryl moiety led to discovery of potent RORγt inhibitors with good oral bioavailability and CNS penetration. Compounds 9a and 9g demonstrated excellent in vivo efficacy in EAE mice dose dependently with once daily oral administration.
RESUMEN
N,N'-Diarylureas were prepared, and the structure-activity relationship relative to the CXCR2 receptor was examined. This led to the identification of a potent and highly selective CXCR2 antagonist, which in addition was shown to be functionally active both in vitro against human neutrophils and in vivo in rabbit models of ear edema and neutropenia.
Asunto(s)
Antiinflamatorios/síntesis química , Compuestos de Fenilurea/síntesis química , Receptores de Interleucina-8B/antagonistas & inhibidores , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Unión Competitiva , Células CHO , Calcio/metabolismo , Quimiocina CXCL1 , Quimiocinas , Factores Quimiotácticos , Quimiotaxis , Cricetinae , Humanos , Hipersensibilidad Tardía/inducido químicamente , Hipersensibilidad Tardía/tratamiento farmacológico , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intercelular , Interleucina-8 , Neutropenia/inducido químicamente , Neutropenia/tratamiento farmacológico , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Neutrófilos/fisiología , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Conejos , Ensayo de Unión Radioligante , Receptores de Interleucina-8A/antagonistas & inhibidores , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of tertiary amines as retinoid-related orphan receptor gamma-t (RORγt) inverse agonists was discovered through agonist/inverse agonist conversion. The level of RORγt inhibition can be enhanced by modulating the conformational disruption of H12 in RORγt LBD. Linker exploration and rational design led to the discovery of more potent indole-based RORγt inverse agonists.
RESUMEN
A novel series of 1,2,4-thiadiazole compounds was discovered as selective S1P(1) agonists. The extensive structure-activity relationship studies for these analogues were reported. Among them, 17g was identified to show high in vitro potency with reasonable free unbound fraction in plasma (F(u) > 0.5%), good brain penetration (BBR > 0.5), and desirable pharmacokinetic properties in mouse and rat. Oral administration of 1 mg/kg 17g resulted in significant peripheral lymphocytes reduction at 4 h after dose and rapid lymphocytes recovery at 24 h. 17g showed a transient lymphopenia profile in the repeated dose study in mouse. In addition, 17g also demonstrated efficacy comparable to that of FTY720 (1) in the mouse EAE model of MS.
Asunto(s)
Inmunosupresores/síntesis química , Inmunosupresores/farmacología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Receptores de Lisoesfingolípidos/agonistas , Tiadiazoles/síntesis química , Tiadiazoles/farmacología , Administración Oral , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Humanos , Inmunosupresores/química , Inmunosupresores/farmacocinética , Recuento de Linfocitos , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Ratas , Receptores de Lisoesfingolípidos/metabolismo , Organismos Libres de Patógenos Específicos , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad , Tiadiazoles/química , Tiadiazoles/farmacocinéticaRESUMEN
Inhibition of mitotic kinesins represents a novel approach for the discovery of a new generation of anti-mitotic cancer chemotherapeutics. We report here the discovery of the first potent and selective inhibitor of centromere-associated protein E (CENP-E) 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide (GSK923295; 1), starting from a high-throughput screening hit, 3-chloro-4-isopropoxybenzoic acid 2. Compound 1 has demonstrated broad antitumor activity in vivo and is currently in human clinical trials.
RESUMEN
A series of N-(2-hydroxy-3-sulfonamidobenzene)-N'-arylcyanoguanidines was prepared. In general, these compounds proved to be potent antagonists of CXCR2 while the selectivity versus CXCR1 ranged from non-selective to >200-fold.
Asunto(s)
Guanidinas/farmacología , Receptores de Interleucina-8A/antagonistas & inhibidores , Receptores de Interleucina-8B/antagonistas & inhibidores , Guanidinas/química , HumanosRESUMEN
A series of 3-substituted N,N'-diarylureas was prepared and the structure-activity relationship relative to CXCR2 receptor affinity as well as their pharmacokinetic properties were examined. In vitro microsomal metabolism studies indicated that the lower clearance rates of the 3-sulfonamido-substituted compounds were most likely due to the suppression of glucuronidation.