The Effect of Multiple Oral Doses of a Glycine Transporter 1 Inhibitor, Iclepertin (BI 425809), on the Steady-state Pharmacokinetics of a Combined Oral Contraceptive Containing Ethinylestradiol and Levonorgestrel: a Phase I Clinical Trial in Healthy Females.

Background: Iclepertin is a selective inhibitor of glycine transporter 1 recently investigated as a novel treatment for cognitive impairment associated with schizophrenia. Iclepertin is a potential mild inducer of liver cytochrome P450 3A4, which metabolises ethinylestradiol and levonorgestrel, which are used in combined oral contraceptives (OCs).

Objectives: This trial investigated the potential drug interaction effect of steady-state iclepertin on the steady-state pharmacokinetics of combined OCs.

Assessing the Effect of Food on the Pharmacokinetics of Iclepertin in Healthy Volunteers: A Phase I, Open-Label, Randomised, Cross-over Trial.

Background And Objectives: Iclepertin, a selective glycine transporter-1 inhibitor, was investigated as a potential treatment for cognitive impairment associated with schizophrenia. The objective of this trial was to determine the effect of food on the pharmacokinetics of iclepertin 10 mg.

Methods: This Phase I, open-label, 2-period cross-over trial randomised (1:1) healthy volunteers to 2 treatment sequences (fasted-fed or fed-fasted) to receive a single oral dose of iclepertin 10 mg once daily in either the fasted or fed state followed by cross-over to the other state.

Utilising Endogenous Biomarkers in Drug Development to Streamline the Assessment of Drug-Drug Interactions Mediated by Renal Transporters: A Pharmaceutical Industry Perspective.

The renal secretion of many drugs is facilitated by membrane transporters, including organic cation transporter 2, multidrug and toxin extrusion protein 1/2-K and organic anion transporters 1 and 3. Inhibition of these transporters can reduce renal excretion of drugs and thereby pose a safety risk. Assessing the risk of inhibition of these membrane transporters by investigational drugs remains a key focus in the evaluation of drug-drug interactions (DDIs).

Mechanistic Static Model based Prediction of Transporter Substrate Drug-Drug Interactions Utilizing Atorvastatin and Rifampicin.

Objective: An in vitro relative activity factor (RAF) technique combined with mechanistic static modeling was examined to predict drug-drug interaction (DDI) magnitude and analyze contributions of different clearance pathways in complex DDIs involving transporter substrates. Atorvastatin and rifampicin were used as a model substrate and inhibitor pair.

Methods: In vitro studies were conducted with transfected HEK293 cells, hepatocytes and human liver microsomes.

Development of BET Inhibitors as Potential Treatments for Cancer: Optimization of Pharmacokinetic Properties.

We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extra-terminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-(H)methyl-1-methyl-1-1,2,3-triazol-5-yl]-5-[()-(oxan-4-yl)(phenyl)methyl]-5-pyrido[3,2-]indol-7-yl}propan-2-ol (), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species.

Development of BET inhibitors as potential treatments for cancer: A new carboline chemotype.

We describe our efforts to introduce structural diversity to a previously described triazole-containing N1-carboline series of bromodomain and extra-terminal (BET) inhibitors. N9 carbolines were designed to retain favorable binding interactions that the N1-carbolines possess. A convergent synthetic route enabled modifications to reduce clearance, enhance physicochemical properties, and improve the overall in vitro profile.

Addition of Optimized Bovine Serum Albumin Level in a High-Throughput Caco-2 Assay Enabled Accurate Permeability Assessment for Lipophilic Compounds.

The Caco-2 permeability assay is a well-accepted in vitro model to evaluate compounds' potential for oral absorption at early discovery. However, for many lipophilic compounds, no meaningful Caco-2 data could be generated due to their low solubility in assay buffer and/or poor recovery from the assay. In our previous study, we reported an organic catch approach to improve compound recovery.