14 research outputs found
Macitentan Attenuates Chronic Mountain Sickness in Rats by Regulating Arginine and Purine Metabolism
3‑((<i>R</i>)‑4-(((<i>R</i>)‑6-(2-Bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)propanoic Acid (HEC72702), a Novel Hepatitis B Virus Capsid Inhibitor Based on Clinical Candidate GLS4
The inhibition of
hepatitis B virus (HBV) capsid assembly is a
novel strategy for the development of chronic hepatitis B (CHB) therapeutics.
On the basis of the preclinical properties and clinical results of
GLS4, we carried out further investigation to seek a better candidate
compound with appropriate anti-HBV potency, reduced hERG activity,
decreased CYP enzyme induction, and improved pharmacokinetic (PK)
properties. To this end, we have successfully found that morpholine
carboxyl analogues with comparable anti-HBV activities to that of
GLS4 showed decreased hERG activities, but they displayed strong CYP3A4
induction in a concentration-dependent manner, except for morpholine
propionic acid analogues. After several rounds of modification, compound <b>58</b> (HEC72702), which had an (<i>R</i>)-morpholine-2-propionic
acid at the C6 position of its dihydropyrimidine core ring, was found
to display no induction of the CYP1A2, CYP3A4, or CYP2B6 enzyme at
the high concentration of 10 μM. In particular, it demonstrated
a good systemic exposure and high oral bioavailability and achieved
a viral-load reduction greater than 2 log in a hydrodynamic-injected
(HDI) HBV mouse model and has now been selected for further development
Transcription factor ISL1 is essential for pacemaker development and function
The sinoatrial node (SAN) maintains a rhythmic heartbeat; therefore, a better understanding of factors that drive SAN development and function is crucial to generation of potential therapies, such as biological pacemakers, for sinus arrhythmias. Here, we determined that the LIM homeodomain transcription factor ISL1 plays a key role in survival, proliferation, and function of pacemaker cells throughout development. Analysis of several Isl1 mutant mouse lines, including animals harboring an SAN-specific Isl1 deletion, revealed that ISL1 within SAN is a requirement for early embryonic viability. RNA-sequencing (RNA-seq) analyses of FACS-purified cells from ISL1-deficient SANs revealed that a number of genes critical for SAN function, including those encoding transcription factors and ion channels, were downstream of ISL1. Chromatin immunoprecipitation assays performed with anti-ISL1 antibodies and chromatin extracts from FACS-purified SAN cells demonstrated that ISL1 directly binds genomic regions within several genes required for normal pacemaker function, including subunits of the L-type calcium channel, Ank2, and Tbx3. Other genes implicated in abnormal heart rhythm in humans were also direct ISL1 targets. Together, our results demonstrate that ISL1 regulates approximately one-third of SAN-specific genes, indicate that a combination of ISL1 and other SAN transcription factors could be utilized to generate pacemaker cells, and suggest ISL1 mutations may underlie sick sinus syndrome