RESUMEN
The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.
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Éteres/farmacología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Tretinoina/farmacología , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Éteres/síntesis química , Éteres/química , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Células Th17 , Tretinoina/síntesis química , Tretinoina/químicaRESUMEN
Aortic valve sclerosis is a highly prevalent, poorly characterized asymptomatic manifestation of calcific aortic valve disease and may represent a therapeutic target for disease mitigation. Human aortic valve cusps and blood were obtained from 333 patients undergoing cardiac surgery (n = 236 for severe aortic stenosis, n = 35 for asymptomatic aortic valve sclerosis, n = 62 for no valvular disease), and a multiplex assay was used to evaluate protein expression across the spectrum of calcific aortic valve disease. A subset of six valvular tissue samples (n = 3 for asymptomatic aortic valve sclerosis, n = 3 for severe aortic stenosis) was used to create RNA sequencing profiles, which were subsequently organized into clinically relevant gene modules. RNA sequencing identified 182 protein-encoding, differentially expressed genes in aortic valve sclerosis vs. aortic stenosis; 85% and 89% of expressed genes overlapped in aortic stenosis and aortic valve sclerosis, respectively, which decreased to 55% and 84% when we targeted highly expressed genes. Bioinformatic analyses identified six differentially expressed genes encoding key extracellular matrix regulators: TBHS2, SPARC, COL1A2, COL1A1, SPP1, and CTGF. Differential expression of key circulating biomarkers of extracellular matrix reorganization was observed in control vs. aortic valve sclerosis (osteopontin), control vs. aortic stenosis (osteoprotegerin), and aortic valve sclerosis vs. aortic stenosis groups (MMP-2), which corresponded to valvular mRNA expression. We demonstrate distinct mRNA and protein expression underlying aortic valve sclerosis and aortic stenosis. We anticipate that extracellular matrix regulators can serve as circulating biomarkers of early calcific aortic valve disease and as novel targets for early disease mitigation, pending prospective clinical investigations.
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Estenosis de la Válvula Aórtica/sangre , Estenosis de la Válvula Aórtica/genética , Válvula Aórtica/metabolismo , Válvula Aórtica/patología , Calcinosis/sangre , Calcinosis/genética , Ácidos Nucleicos Libres de Células/metabolismo , Osteopontina/metabolismo , Osteoprotegerina/metabolismo , Transcriptoma , Anciano , Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/cirugía , Secuencia de Bases , Biomarcadores/metabolismo , Calcinosis/cirugía , Estudios de Casos y Controles , Ácidos Nucleicos Libres de Células/genética , Matriz Extracelular/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteopontina/genética , Osteoprotegerina/genética , ARN Mensajero/genética , RNA-SeqRESUMEN
RORγt is the master regulator of the IL-23/IL-17 axis, a pathway that is clinically validated for the treatment of various immunological disorders. Over the last few years, our group has reported different chemotypes that potently act as inverse agonists of RORγt. One of them, the tricyclic pyrrolidine chemotype, has demonstrated biologic-like preclinical efficacy and has led to our clinical candidate BMS-986251. In this letter, we discuss the invention of an annulation reaction which enabled the synthesis of a tricyclic exocyclic amide chemotype and the identification of compounds with RORγt inverse agonist activity. Preliminary structure activity relationships are disclosed.
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Amidas/química , Hidrocarburos Cíclicos/química , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Sulfonas/química , Amidas/síntesis química , Amidas/metabolismo , Animales , Ciclización , Agonismo Inverso de Drogas , Humanos , Hidrocarburos Cíclicos/síntesis química , Hidrocarburos Cíclicos/metabolismo , Ratones , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/metabolismoRESUMEN
In an effort to discover oral inverse agonists of RORγt to treat inflammatory diseases, a new 2,6-difluorobenzyl ether series of cyclopentyl sulfones were found to be surprisingly more potent than the corresponding alcohol derivatives. When combined with a more optimized phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone template, the 2,6-difluorobenzyl ethers yielded a set of very potent RORγt inverse agonists (e.g., compound 26, RORγt Gal4 EC50 11 nM) that are highly selective against PXR, LXRα and LXRß. After optimizing for stability in human and mouse liver microsomes, compounds 29 and 38 were evaluated in vivo and found to have good oral bioavailability (56% and 101%, respectively) in mice. X-ray co-crystal structure of compound 27 in RORγt revealed that the bulky benzyl ether group causes helix 11 of the protein to partially uncoil to create a new, enlarged binding site, which nicely accommodates the benzyl ether moiety, leading to net potency gain.
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Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Pirrolidinas/farmacología , Sulfonas/farmacología , Animales , Cristalografía por Rayos X , Descubrimiento de Drogas , Agonismo Inverso de Drogas , Estabilidad de Medicamentos , Células Hep G2 , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Estructura Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/metabolismo , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/metabolismoRESUMEN
A novel series of cis-3,4-diphenylpyrrolidines were designed as RORγt inverse agonists based on the binding conformation of previously reported bicyclic sulfonamide 1. Preliminary synthesis and structure-activity relationship (SAR) study established (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidine as the most effective scaffold. Subsequent SAR optimization led to identification of a piperidinyl carboxamide 31, which was potent against RORγt (EC50 of 61 nM in an inverse agonist assay), selective relative to RORα, RORß, LXRα and LXRß, and stable in human and mouse liver microsomes. Furthermore, compound 31 exhibited considerably lower PXR Ymax (46%) and emerged as a promising lead. The binding mode of the diphenylpyrrolidine series was established with an X-ray co-crystal structure of 10A/RORγt.
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Diseño de Fármacos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Pirrolidinas/química , Animales , Sitios de Unión , Cristalografía por Rayos X , Agonismo Inverso de Drogas , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Simulación de Dinámica Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Receptor X de Pregnano/agonistas , Receptor X de Pregnano/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/metabolismo , Relación Estructura-ActividadRESUMEN
Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.
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Compuestos de Bencilo/farmacología , Compuestos Heterocíclicos/farmacología , Receptores de Ácido Retinoico/agonistas , Animales , Compuestos de Bencilo/química , Relación Dosis-Respuesta a Droga , Femenino , Compuestos Heterocíclicos/química , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Relación Estructura-Actividad , Receptor de Ácido Retinoico gammaRESUMEN
In order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of RORγt inverse agonists, a late-stage bromination was employed. Although not regioselective, the bromination protocol allowed us to explore new substitution patterns/vectors that otherwise would have to be incorporated at the very beginning of the synthesis. Based on the SAR obtained from this exercise, compound 15 bearing a C8 fluorine was developed as a very potent and selective RORγt inverse agonist. This analog's in vitro profile, pharmacokinetic (PK) data and efficacy in an IL-23 induced mouse acanthosis model will be discussed.
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Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Melanosis/tratamiento farmacológico , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Sulfonas/uso terapéutico , Animales , Cristalografía por Rayos X , Agonismo Inverso de Drogas , Femenino , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Interleucina-18 , Masculino , Melanosis/inducido químicamente , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Estructura Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Unión Proteica , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/farmacocinéticaRESUMEN
An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.
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Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Pirrolidinas/farmacología , Sulfonas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Agonismo Inverso de Drogas , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Pirrolidinas/administración & dosificación , Pirrolidinas/química , Relación Estructura-Actividad , Sulfonas/administración & dosificación , Sulfonas/químicaRESUMEN
We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.
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Compuestos Bicíclicos con Puentes/farmacología , Diseño de Fármacos , Propanoles/farmacología , Receptores de Ácido Retinoico/agonistas , Receptores de Esteroides/agonistas , Sulfonamidas/farmacología , Animales , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Receptores X del Hígado/agonistas , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Receptor X de Pregnano , Propanoles/síntesis química , Propanoles/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Receptor de Ácido Retinoico gammaRESUMEN
The synthesis and structure-activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.
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Artritis Experimental/tratamiento farmacológico , Lisofosfolípidos/agonistas , Esfingosina/análogos & derivados , Relación Estructura-Actividad , Administración Oral , Animales , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Humanos , Isoxazoles/química , Isoxazoles/farmacología , Recuento de Linfocitos , Masculino , Ratas Endogámicas Lew , Receptores de Lisoesfingolípidos/agonistas , Esfingosina/agonistasRESUMEN
A series of compounds which exhibited good human CCR1 binding and functional potency was modified resulting in the discovery of a novel series of high affinity, functionally potent antagonists of the CCR1 receptor. Issues of PXR activity, ion-channel potency, and poor metabolic stability were addressed by the addition of a hydroxyl group to an otherwise lipophilic area in the molecule resulting in the discovery of preclinical candidate BMS-457 for the treatment of rheumatoid arthritis.
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Descubrimiento de Drogas , Piperidinas/farmacología , Receptores CCR1/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Relación Estructura-ActividadRESUMEN
BMS-813160 (compound 3) was identified as a potent and selective CCR2/5 dual antagonist. Compound 3 displayed good permeability at pH = 7.4 in PAMPA experiments and demonstrated excellent human liver microsome stability. Pharmacokinetic studies established that 3 had excellent oral bioavailability and exhibited low clearance in dog and cyno. Compound 3 was also studied in the mouse thioglycollate-induced peritonitis model, which confirmed its ability to inhibit the migration of inflammatory monocytes and macrophages. As a result of this profile, compound 3 was selected as a clinical candidate.
RESUMEN
AIMS: Enhanced risk stratification of patients with aortic stenosis (AS) is necessary to identify patients at high risk for adverse outcomes, and may allow for better management of patient subgroups at high risk of myocardial damage. The objective of this study was to identify plasma biomarkers and multimarker profiles associated with adverse outcomes in AS. METHODS AND RESULTS: We studied 708 patients with calcific AS and measured 49 biomarkers using a Luminex platform. We studied the correlation between biomarkers and the risk of (i) death and (ii) death or heart failure-related hospital admission (DHFA). We also utilized machine-learning methods (a tree-based pipeline optimizer platform) to develop multimarker models associated with the risk of death and DHFA. In this cohort with a median follow-up of 2.8 years, multiple biomarkers were significantly predictive of death in analyses adjusted for clinical confounders, including tumour necrosis factor (TNF)-α [hazard ratio (HR) 1.28, P < 0.0001], TNF receptor 1 (TNFRSF1A; HR 1.38, P < 0.0001), fibroblast growth factor (FGF)-23 (HR 1.22, P < 0.0001), N-terminal pro B-type natriuretic peptide (NT-proBNP) (HR 1.58, P < 0.0001), matrix metalloproteinase-7 (HR 1.24, P = 0.0002), syndecan-1 (HR 1.27, P = 0.0002), suppression of tumorigenicity-2 (ST2) (IL1RL1; HR 1.22, P = 0.0002), interleukin (IL)-8 (CXCL8; HR 1.22, P = 0.0005), pentraxin (PTX)-3 (HR 1.17, P = 0.001), neutrophil gelatinase-associated lipocalin (LCN2; HR 1.18, P < 0.0001), osteoprotegerin (OPG) (TNFRSF11B; HR 1.26, P = 0.0002), and endostatin (COL18A1; HR 1.28, P = 0.0012). Several biomarkers were also significantly predictive of DHFA in adjusted analyses including FGF-23 (HR 1.36, P < 0.0001), TNF-α (HR 1.26, P < 0.0001), TNFR1 (HR 1.34, P < 0.0001), angiopoietin-2 (HR 1.26, P < 0.0001), syndecan-1 (HR 1.23, P = 0.0006), ST2 (HR 1.27, P < 0.0001), IL-8 (HR 1.18, P = 0.0009), PTX-3 (HR 1.18, P = 0.0002), OPG (HR 1.20, P = 0.0013), and NT-proBNP (HR 1.63, P < 0.0001). Machine-learning multimarker models were strongly associated with adverse outcomes (mean 1-year probability of death of 0%, 2%, and 60%; mean 1-year probability of DHFA of 0%, 4%, 97%; P < 0.0001). In these models, IL-6 (a biomarker of inflammation) and FGF-23 (a biomarker of calcification) emerged as the biomarkers of highest importance. CONCLUSIONS: Plasma biomarkers are strongly associated with the risk of adverse outcomes in patients with AS. Biomarkers of inflammation and calcification were most strongly related to prognosis.
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Estenosis de la Válvula Aórtica , Calcinosis , Insuficiencia Cardíaca , Biomarcadores , Humanos , Péptido Natriurético Encefálico , Fragmentos de Péptidos , PronósticoRESUMEN
SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound 1 (BMS-986251) led to tricyclic-carbocyclic analogues represented by 3-7 and culminated in the identification of 3d (BMS-986313), with structural differences distinct from 1. The X-ray co-crystal structure of 3d with the ligand binding domain of RORγt revealed several key interactions, which are different from 1. The in vitro and in vivo PK profiles of 3d are described. In addition, we demonstrate robust efficacy of 3d in two preclinical models of psoriasis-the IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with 3d in these models is comparable to the results observed with 1.
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Amidas/uso terapéutico , Hidrocarburos Cíclicos/uso terapéutico , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Psoriasis/tratamiento farmacológico , Amidas/química , Amidas/farmacocinética , Animales , Agonismo Inverso de Drogas , Femenino , Humanos , Hidrocarburos Cíclicos/química , Hidrocarburos Cíclicos/farmacocinética , Interleucina-23 , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Estructura Molecular , Psoriasis/inducido químicamente , Ratas , Relación Estructura-ActividadRESUMEN
INTRODUCTION: Murine transverse aortic constriction (TAC) is a frequently used model of pressure overload-induced left ventricular (LV) remodeling. However, there is considerable variability in disease progression to overt heart failure (HF) development in the most commonly used strain of mice (i.e., C57BL/6J). Studies have shown that C57BL/6J mice are more resistant than BALB/c mice to congestive HF development following myocardial infarction or angiotensin II-induced hypertension. Therefore, we tested the hypothesis that BALB/c mice may be a better research model to study TAC-induced progressive HF. METHODS: Following sham or TAC surgery in both C57BL/6J (n = 29) and BALB/c (n = 32) mice, we evaluated cardiac dimensions and function by echocardiography at 2, 4, 8, and 12 weeks and monitored survival throughout the study. In a separate cohort of BALB/c mice, we repeated the study in the presence of the angiotensin converting enzyme inhibitor enalapril or a vehicle initiated 2 weeks post-TAC and administered for 6 weeks. At the end of the studies, we assessed the heart weight, lung weight, and plasma brain natriuretic peptide (BNP) concentration. RESULTS: Following comparable TAC, both C57BL/6J and BALB/c mice showed significant LV remodeling compared with the sham control mice. BALB/c mice progressively developed systolic dysfunction, LV dilation, lung congestion, and significant mortality, whereas C57BL/6J mice did not. In the separate cohort of BALB/c TAC mice, enalapril significantly reduced the heart weight, lung weight, and plasma BNP concentration and improved survival compared with the vehicle control. DISCUSSION: BALB/c mice uniformly developed congestive HF post-TAC. Enalapril was effective in improving survival and reducing lung congestion in this model. The data suggest that BALB/c mice may be a better research tool than C57BL/6J mice to study TAC-induced disease progression to HF and to evaluate novel therapies for the treatment of chronic HF with reduced ejection fraction.
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Aorta/fisiopatología , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/fisiopatología , Ratones Endogámicos BALB C/fisiología , Remodelación Ventricular/fisiología , Animales , Constricción , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Enalapril/farmacología , Enalapril/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/patología , Ventrículos Cardíacos/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL/fisiología , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/fisiología , Remodelación Ventricular/efectos de los fármacosRESUMEN
Little data are available regarding the determinants and prognostic significance of serum albumin in Heart Failure with Preserved Ejection Fraction (HFpEF). We sought to examine the phenotypic correlates of albumin and its independent prognostic implications in HFpEF. We analyzed data from 3,254 subjects enrolled the TOPCAT trial. We stratified subjects according to tertiles of albumin and examined differences in various phenotypic traits between these strata, including 8 protein biomarkers selected ad hoc and measured from frozen samples available in a subset of participants (nâ¯=â¯372). We also assessed the relationship between albumin and the trial primary endpoint. Lower albumin was associated with older age, black race, and greater prevalence of NYHA class III-IV, peripheral arterial disease, atrial fibrillation and diabetes mellitus. Lower albumin was also associated with increased levels of several inflammatory biomarkers, markers of liver fibrosis, albuminuria, and greater arterial stiffness, diastolic dysfunction and pulmonary hypertension. Albumin was a strong predictor of the primary trial endpoint, even after adjustment for the MAGGIC risk score (hazard ratio [HR] 0.72, confidence interval [CI] 0.67 to 0.78; p <0.0001) and prespecified traditional risk factors (HR 0.78, CI 0.71 to 0.85; p <0.0001). Lower albumin was strongly associated with a worse prognosis even well within normal ranges (>3.5 g/dL), with a sharp increase in risk between 4.6 and 3.6 g/dL. In conclusion, albumin is an integrated marker of various adverse processes in HFpEF, including inflammation, subclinical liver disease, arterial stiffness, and renal disease. Albumin is a powerful risk predictor independent of traditional risk prediction models, even within normal ranges.
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Biomarcadores/metabolismo , Insuficiencia Cardíaca/metabolismo , Albúmina Sérica/metabolismo , Anciano , Método Doble Ciego , Femenino , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Pronóstico , Factores de Riesgo , Espironolactona/uso terapéutico , Volumen SistólicoRESUMEN
OBJECTIVES: This study sought to assess if clinical phenogroups differ in comprehensive biomarker profiles, cardiac and arterial structure/function, and responses to spironolactone therapy. BACKGROUND: Previous studies identified distinct subgroups (phenogroups) of patients with heart failure with preserved ejection fraction (HFpEF). METHODS: Among TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial) participants, we performed latent-class analysis to identify HFpEF phenogroups based on standard clinical features and assessed differences in multiple biomarkers measured from frozen plasma; cardiac and arterial structure/function measured with echocardiography and arterial tonometry; prognosis; and response to spironolactone. RESULTS: Three HFpEF phenogroups were identified. Phenogroup 1 (n = 1,214) exhibited younger age, higher prevalence of smoking, preserved functional class, and the least evidence of left ventricular (LV) hypertrophy and arterial stiffness. Phenogroup 2 (n = 1,329) was older, with normotrophic concentric LV remodeling, atrial fibrillation, left atrial enlargement, large-artery stiffening, and biomarkers of innate immunity and vascular calcification. Phenogroup 3 (n = 899) demonstrated more functional impairment, obesity, diabetes, chronic kidney disease, concentric LV hypertrophy, high renin, and biomarkers of tumor necrosis factor-alpha-mediated inflammation, liver fibrosis, and tissue remodeling. Compared with phenogroup 1, phenogroup 3 exhibited the highest risk of the primary endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest (hazard ratio [HR]: 3.44; 95% confidence interval [CI]: 2.79 to 4.24); phenogroups 2 and 3 demonstrated similar all-cause mortality (phenotype 2 HR: 2.36; 95% CI: 1.89 to 2.95; phenotype 3 HR: 2.26, 95% CI: 1.77 to 2.87). Spironolactone randomized therapy was associated with a more pronounced reduction in the risk of the primary endpoint in phenogroup 3 (HR: 0.75; 95% CI: 0.59 to 0.95; p for interaction = 0.016). Results were similar after excluding participants from Eastern Europe. CONCLUSIONS: We identified important differences in circulating biomarkers, cardiac/arterial characteristics, prognosis, and response to spironolactone across clinical HFpEF phenogroups. These findings suggest distinct underlying mechanisms across clinically identifiable phenogroups of HFpEF that may benefit from different targeted interventions.
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Insuficiencia Cardíaca/tratamiento farmacológico , Espironolactona/uso terapéutico , Volumen Sistólico/fisiología , Remodelación Ventricular/fisiología , Anciano , Ecocardiografía , Femenino , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Fenotipo , Pronóstico , Resultado del Tratamiento , Remodelación Ventricular/efectos de los fármacosRESUMEN
BACKGROUND: Better risk stratification strategies are needed to enhance clinical care and trial design in heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: The purpose of this study was to assess the value of a targeted plasma multi-marker approach to enhance our phenotypic characterization and risk prediction in HFpEF. METHODS: In this study, the authors measured 49 plasma biomarkers from TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial participants (n = 379) using a Multiplex assay. The relationship between biomarkers and the risk of all-cause death or heart failure-related hospital admission (DHFA) was assessed. A tree-based pipeline optimizer platform was used to generate a multimarker predictive model for DHFA. We validated the model in an independent cohort of HFpEF patients enrolled in the PHFS (Penn Heart Failure Study) (n = 156). RESULTS: Two large, tightly related dominant biomarker clusters were found, which included biomarkers of fibrosis/tissue remodeling, inflammation, renal injury/dysfunction, and liver fibrosis. Other clusters were composed of neurohormonal regulators of mineral metabolism, intermediary metabolism, and biomarkers of myocardial injury. Multiple biomarkers predicted incident DHFA, including 2 biomarkers related to mineral metabolism/calcification (fibroblast growth factor-23 and OPG [osteoprotegerin]), 3 inflammatory biomarkers (tumor necrosis factor-alpha, sTNFRI [soluble tumor necrosis factor-receptor I], and interleukin-6), YKL-40 (related to liver injury and inflammation), 2 biomarkers related to intermediary metabolism and adipocyte biology (fatty acid binding protein-4 and growth differentiation factor-15), angiopoietin-2 (related to angiogenesis), matrix metalloproteinase-7 (related to extracellular matrix turnover), ST-2, and N-terminal pro-B-type natriuretic peptide. A machine-learning-derived model using a combination of biomarkers was strongly predictive of the risk of DHFA (standardized hazard ratio: 2.85; 95% confidence interval: 2.03 to 4.02; p < 0.0001) and markedly improved the risk prediction when added to the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure Risk Score) risk score. In an independent cohort (PHFS), the model strongly predicted the risk of DHFA (standardized hazard ratio: 2.74; 95% confidence interval: 1.93 to 3.90; p < 0.0001), which was also independent of the MAGGIC risk score. CONCLUSIONS: Various novel circulating biomarkers in key pathophysiological domains are predictive of outcomes in HFpEF, and a multimarker approach coupled with machine-learning represents a promising strategy for enhancing risk stratification in HFpEF.
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Biomarcadores/sangre , Insuficiencia Cardíaca/sangre , Aprendizaje Automático , Anciano , Femenino , Insuficiencia Cardíaca/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Medición de Riesgo , Estados Unidos/epidemiologíaRESUMEN
Employing a virtual screening approach, we identified the pyroglutamide moiety as a nonacid replacement for the cyclohexanecarboxylic acid group which, when coupled to our previously reported conformationally locked tricyclic core, provided potent and selective RORγt inverse agonists. Structure-activity relationship optimization of the pyroglutamide moiety led to the identification of compound 18 as a potent and selective RORγt inverse agonist, albeit with poor aqueous solubility. We took advantage of the tertiary carbinol group in 18 to synthesize a phosphate prodrug, which provided good solubility, excellent exposures in mouse PK studies, and significant efficacy in a mouse model of psoriasis.
RESUMEN
Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5, which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate.