IndraLab

"Containers 26 and 27 show no evidence of hERG ion channel inhibition up to 25 mM which paves the way for their further development."

"Such improvements had been the primary focus of the synthetic program and were reflected in reduced hERG ion channel inhibition compared to 1 ."

"Moderate in vitro cytochrome P450 (CYP) and potassium ion channel Kv11.1 (hERG) inhibition were uncovered as potential liabilities for the chemical series."

"It exhibits a low human ether-a-go-go-related gene (hERG) ion channel inhibition, excellent systemic exposure, crosses the blood-brain barrier in mice when administered orally, and BKI-1553 treatment lead to reduced parasite burden in the brain, lungs and liver of T. gondii infected mice ( xref )."

"Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series."

"However, the safety pharmacology data were notencouraging, as 25 inhibited CYP3A4 and the hERG ion channel, arousingconcern for potential drug–drug interactions and cardiac liabilities."

"As expected, the hERG ion channel is inhibited by E-4031 at nanomolar concentrations whereas no concentration dependent inhibition is observed for M3 at concentrations up to 25 μM. The calculated IC50 value for E-4031 is 267 nM whereas for M3 the IC50 is higher than 25 μM. Compounds with hERG ion channel inhibition IC50 values below 100 nM are classified as highly potent whereas those with IC50 values above 10 μM are categorized as having little to no inhibitory activity.[ xref ]Given the lack of hERG ion channel inhibition activity of M3 we proceeded to test the mutagenicity of M3 ."

"As mentioned, 6 and 12 both had reduced hERG ion channel inhibition compared to 1 , which had been the primary focus for the synthetic program."

"In most reported HDAC6 inhibitors including the molecules described above, the ZBG is hydroxamate, which may cause suboptimal pharmacokinetics, non-selective interaction such as hERG cardiac ion channel inhibition, and mutagenicity xref ."

"SAR studies of this ion channel have shed light on the structural requirements for hERG interaction but most importantly may reveal drug design principles to reduce hERG affinity."

"Given the improvements related to hERG ion channel inhibition seen in 6 , changes were made with the 2-oxa-6-azaspiro[3.4]octane at P 3 ."

"Acyclic CB[ n ]-type receptors are composed of a central glycoluril oligomer building block, two aromatic walls, and peripheral solubilizing groups which has allowed extensive structure-binding affinity relationships to be built up. xref – xref Our earliest acyclic CB[ n ]-type receptor ( ACB1 ) was based on glycoluril tetramer, o -xylylene walls, and peripheral carboxylic acids groups; ACB1 possessed poor aqueous solubility (≤ 2 mM). xref In contrast, host M1 with SO 3 Na groups displays an anomalously high solubility of 346 mM in water which enabled its use as a solubilizing excipient for insoluble drugs and was used to deliver albendazole to mice in vivo . xref , xref Host M1 was shown to be biocompatible according to the standard in vitro (e.g. metabolic and cell death, Ames test, lack of hERG ion channel inhibition) and in vivo (e.g. maximum tolerated dose, blood gas and blood pH, mean artertial pressue) assays. xref , xref More recently, we have shown that M1 and analogues function as in vivo reversal agents for neuromuscular block induced by rocuronium, vecuronium, and cisatracurium and for the hyperlocomotion induced by the drug of abuse methamphetamine. xref , xref , xref In ongoing work, we aim to optimize the structure of acyclic CB[ n ]-type receptors for use in these biomedical applications."

"Accordingly, new chemical entities are typically screened for hERG ion channel inhibition early in the drug development process.[ xref ]The ability of TetM0 to inhibit the hERG ion channel (six concentrations from 0.008 μM to 25 μM) was evaluated via the patch-clamp technique (QPatch HTX)."

"The compounds are structurally related to a series we disclosed previously, but are improved with respect to cytochrome P-450 enzyme (CYP) and potassium ion channel Kv11.1 (hERG) inhibition and synthetic accessibility."

"M1 and related compounds display excellent biocompatibility according to both in vitro (metabolic and cell death assays; no mutagenicity by Ames test; lack of hERG ion channel inhibition) and in vivo (e.g. maximum tolerated dose; blood pH and blood gas analysis; mean arterial pressure; urinary excretion) tests. xref – xref , xref Acyclic CB[n] compounds also function as components of sensing ensembles for biologically active substances like nitrosamines and over the counter drugs. xref Given the high affinity of (acyclic) CB[n]-type receptors toward their guests, we envisioned they could also be used as in vivo reversal agents for appropriate targets similar to the use of Sugammadex to reverse neuromuscular block. xref Indeed, we found that acyclic CB[n] dose dependently reversed the in vivo biological effect of the neuromuscular blockers rocuronium, vecuronium, and cisatracurium as well as the depth of anesthesia after treatment with ketamine. xref – xref Conceptually related sequestration and reversal applications using macrocyclic CB[n] have been investigated in the laboratory of Prof."

"Potential hERG ion channel inhibition was calibrated using in vitro patch clamp assays and steered molecular dynamics (SMD) simulations were used to examine membrane permeability of a subset of compounds."

"The results indicate that considering only the hERG ion channel inhibition of only the parent drug is potentially misleading, and the inclusion of active metabolite data and the influence of other ion channel currents should be considered to improve the prediction of potential cardiac toxicity."

"These studies showed that tetrahydroindazole 22d displayed an adequate cytochrome P450 inhibition profile ( xref ), as well as acceptable hERG ion channel inhibition potential (all IC 50 values > 1 μM)."

"The novel N-alkylated pyrazole portion offered improved physicochemical properties, and optimization led to identification of a zwitterion series, exemplified by lead 29 , with decreased HepG2 cytotoxicity as well as limited hERG ion channel inhibition."

"Incorporation of a 6-azaindole afforded a marked increase in cellular potency but was associated with poor PK and hERG ion channel inhibition."

"Numerous variants have been created, by us and others, that differ in the nature of the central glycoluril oligomer, the terminal aromatic walls, and the appended solubilizing groups. xref , xref Of the acyclic CB[n] based on glycoluril tetramer prepared to date, Tet1 and Tet2 have been used extensively because of their high binding affinity which has enabled their function as solubilizing excipients for insoluble drugs and as in vivo sequestration agents for neuromuscular blockers (e.g. rocuronium and vecuronium) xref , xref and drugs of abuse such as methamphetamine. xref Host Tet1 has displayed excellent biocompatibility according to the usual in vitro (e.g. cell death and metabolic activity, mutagenicity, lack of hERG ion channel inhibition) and in vivo (e.g. maximum tolerated dose, blood gases, blood pH, mean arterial pressure) assays. xref The group of Prof."