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There are concerns about the potential effect of social distancing used to control COVID-19 on the incidence of cardiovascular diseases (CVD). Retrospective cohort study. We examined the association between lockdown and CVD incidence in a Zero-COVID country, New Caledonia. Inclusion criteria were defined by a positive troponin sample during hospitalization. The study period lasted for 2 months, starting March 20, 2020 (strict lockdown: first month; loose lockdown: second month) compared with the same period of the three previous years to calculate incidence ratio (IR). Demographic characteristics and main CVD diagnoses were collected. The primary endpoint was the change in incidence of hospital admission with CVD during lockdown compared with the historical counterpart. The secondary endpoint included influence of strict lockdown, change in incidence of the primary endpoint by disease, and outcome incidences (intubation or death) analyzed with inverse probability weighting method. A total of 1215 patients were included: 264 in 2020 vs 317 (average of the historical period). CVD hospitalizations were reduced during strict lockdown (IR 0.71 [0.58–0.88]), but not during loose lockdown (IR 0.94 [0.78–1.12]). The incidence of acute coronary syndromes was similar in both periods. The incidence of acute decompensated heart failure was reduced during strict lockdown (IR 0.42 [0.24–0.73]), followed by a rebound (IR 1.42 [1–1.98]). There was no association between lockdown and short-term outcomes. Our study showed that lockdown was associated with a striking reduction in CVD hospitalizations, independently from viral spread, and a rebound of acute decompensated heart failure hospitalizations during looser lockdown. [ABSTRACT FROM AUTHOR]

Retinoic acid-related orphan receptor γt (RORγt) is a key master regulator of the differentiation and activation of IL-17 producing CD4 + Th17, CD8 + Tc17 and IL-17/IFN-γ co-producing cells (Th1/17 cells). These cells play critical roles in the pathogenesis of autoimmune diseases such as inflammatory bowel disease and multiple sclerosis. Thus, RORγt is an attractive target for the treatment of these diseases. We discovered TAK-828F, an orally available potent and selective RORγt inverse agonist. The inhibitory effect on the activation and differentiation of Th17 cells by TAK-828F was evaluated in mouse and human primary cells. TAK-828F inhibited IL-17 production from mouse splenocytes and human peripheral blood mononuclear cells dose-dependently at concentrations of 0.01–10 μM without affecting the production of IFN-γ. Additionally, TAK-828F strongly inhibited Th17, Tc17 and Th1/17 cells’ differentiation from naive T cells and memory CD4 + T cells at 100 nM without affecting Th1 cells’ differentiation. In addition, TAK-828F improved Th17/Treg cells’ population ratio by inhibiting Th17 cells’ differentiation and up-regulating Treg cells. Furthermore, TAK-828F, at 100 nM, reduced the production of Th17-related cytokines (IL-17, IL-17F and IL-22) without affecting IFN-γ production in whole blood. These results demonstrate that TAK-828F has the potent and selective inhibitory activity against RORγt both in mouse and human cells. Additionally, oral administration of TAK-828F showed promising efficacy in naive T cell transfer mouse colitis model. TAK-828F may provide a novel therapeutic option to treat immune diseases by inhibiting Th17 and Th1/17 cells’ differentiation and improving imbalance between Th17 and Treg cells. [ABSTRACT FROM AUTHOR]

Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1 , was discovered by high-throughput screening of our compound library. The structure–activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity. The carbazole moiety of 1 was also optimized; a quinazolinedione derivative 18i suppressed the increase of IL-17A mRNA level in the lymph node of a rat model of experimental autoimmune encephalomyelitis (EAE) upon oral administration. These results indicate that the novel quinazolinedione derivatives have great potential as orally available small-molecule RORγt inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with RORγt protein was also observed. [ABSTRACT FROM AUTHOR]

A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay. [ABSTRACT FROM AUTHOR]

A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1 . ( R )- N -(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy- N -methylisoxazole-5-carboxamide ( 22 ) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORγt in a mouse PD (pharmacodynamic) model upon oral administration. [ABSTRACT FROM AUTHOR]

[Display omitted] A series of novel thiazole-containing amides were synthesized. A structure–activity relationship study of these compounds led to the identification of potent and selective Pf FPPS/GGPPS inhibitors with good in vitro ADME profiles. The most promising candidate molecules were progressed to mouse in vivo PK studies and demonstrated adequate free drug exposure to warrant further investigation. [ABSTRACT FROM AUTHOR]