RESUMEN
Biaryl amides as new RORγt modulators were discovered. The crystal structure of biaryl amide agonist 6 in complex with RORγt ligand binding domain (LBD) was resolved, and both "short" and "long" inverse agonists were obtained by removing from 6 or adding to 6 a proper structural moiety. While "short" inverse agonist (8) recruits a corepressor peptide and dispels a coactivator peptide, "long" inverse agonist (9) dispels both. The two types of inverse agonists can be utilized as potential tools to study mechanisms of Th17 transcriptional network inhibition and related disease biology.
RESUMEN
CXCR2 has emerged as a therapeutic target for not only peripheral inflammatory diseases but also neurological abnormalities in the central nervous system (CNS). Herein, we describe the discovery of a novel 1-cyclopentenyl-3-phenylurea series as potent and CNS penetrant CXCR2 antagonists. Extensive SAR studies, wherein molecules' property forecast index (PFI) was carefully optimized for overall balanced developability profiles, led to the discovery of the advanced lead compound 68 with a desirable PFI. Compound 68 demonstrated good in vitro pharmacology with excellent selectivity over CXCR1 and other chemokine receptors. Rat and dog pharmacokinetics (PK) revealed good oral bioavailability, high oral exposure, and desirable elimination half-life of the compound in both species. In addition, the compound demonstrated dose-dependent efficacy in the in vivo pharmacology neutrophil infiltration "air pouch" model in rodents after oral administration. Further, compound 68 is a CNS penetrant molecule with high unbound fraction in brain tissue.
Asunto(s)
Encéfalo/metabolismo , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/farmacología , Receptores de Interleucina-8B/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Antígeno CD11b/biosíntesis , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Semivida , Humanos , Células de Riñón Canino Madin Darby , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Infiltración Neutrófila/efectos de los fármacos , Compuestos de Fenilurea/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
IκB kinase ß (IKKß or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and physicochemical properties and have identified compounds 24 and (R)-28 as having robust in vivo activity.
RESUMEN
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 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
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
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
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
We identified three retinoid-related orphan receptor gamma t (RORγt)-specific inhibitors that suppress T helper 17 (Th17) cell responses, including Th17-cell-mediated autoimmune disease. We systemically characterized RORγt binding in the presence and absence of drugs with corresponding whole-genome transcriptome sequencing. RORγt acts as a direct activator of Th17 cell signature genes and a direct repressor of signature genes from other T cell lineages; its strongest transcriptional effects are on cis-regulatory sites containing the RORα binding motif. RORγt is central in a densely interconnected regulatory network that shapes the balance of T cell differentiation. Here, the three inhibitors modulated the RORγt-dependent transcriptional network to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target loci, the other two inhibitors affected transcription predominantly without removing DNA binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity.
Asunto(s)
Bencenoacetamidas/farmacología , Compuestos de Bencidrilo/farmacología , Digoxina/farmacología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Redes Reguladoras de Genes/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Esclerosis Múltiple/tratamiento farmacológico , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Subgrupos de Linfocitos T/efectos de los fármacos , Células Th17/efectos de los fármacos , Androstenoles/química , Animales , Bencenoacetamidas/química , Compuestos de Bencidrilo/química , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Linaje de la Célula/efectos de los fármacos , Citocinas/metabolismo , Digoxina/química , Encefalomielitis Autoinmune Experimental/inmunología , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Esclerosis Múltiple/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Fragmentos de Péptidos/inmunología , Unión Proteica/efectos de los fármacos , Relación Estructura-Actividad , Biología de Sistemas , Subgrupos de Linfocitos T/inmunología , Células Th17/inmunología , Transcripción Genética/efectos de los fármacos , Activación Transcripcional/efectos de los fármacosRESUMEN
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
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
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
In work directed toward a total synthesis of chartelline A (1a), a strategy was investigated to construct the 10-membered ring of this marine alkaloid via an intramolecular aldehyde/beta-lactam cyclocondensation to form the macrocyclic enamide functionality. Therefore, spiro-beta-lactam and imidazole fragments were first prepared. Tribromooxindole beta-lactam 24 was synthesized from commercially available 5-nitroisatin (18) in seven steps and 30% overall yield via a Staudinger ketene-imine [2 + 2]-cycloaddition strategy. The requisite 2-bromoimidazole subunit 40 bearing a terminal alkyne and a masked aldehyde was efficiently prepared from the readily available imidazole ester 25 in 10 steps. With both advanced intermediates available, the addition of the lithium acetylide generated from 2-bromoimidazole subunit 40 to the gamma-lactam carbonyl group of N-Boc-tribromooxindole 24 was investigated, affording the desired N-Boc-aminal 41. Hydrolysis of the acetonide moiety of 41, followed by oxidative cleavage of the resulting diol, gave the aldehyde 42. Unfortunately, treatment of aldehyde 42 with p-toluenesulfonic acid did not give the desired 10-membered macrocyclic (Z)-enamide 46, but rather the highly unsaturated seven-membered ring compound 44.