Mitsubishi Group (Japan)

This paper reports the first example of a one-pot asymmetric sulfoxidation using in situ generated H2O2. This reaction is catalyzed by two homogeneous catalysts: a Rh complex for the direct synthesis of H2O2 from H2 and O2, and a V complex for the asymmetric oxidation of sulfides.

The crystalline sponge method enables single-crystal X-ray diffraction analysis of guests absorbed within single-crystalline porous materials. However, its application with large or highly polar guests remains challenging. In this study, we addressed some of these limitations using palladium-based octahedron-shaped M6L4 (Td) coordination cages as crystalline sponges. The key to facilitate the crystallization of the cage is the addition of large aromatic polysulfonates ('sticker' anions); the symmetry mismatch between the cage and the sticker (D2h) results in a low-symmetry space group (P ), preventing guest disorder and leading to the formation of guest-accessible channels in the crystal. Guests can be encapsulated either before or after cage crystallization. The size and host-guest properties of the cavity enable analysis of a broad range of compounds, including water-soluble molecules, large amphiphilic molecules (molecular weight of ~1,200) and molecular aggregates. We have demonstrated the versatility of the cage-sticker strategy through its application to a triaugmented triangular-prism-shaped M9L6 cage, extending the guest scope to medium-sized pharmaceutical molecules.

Dersimelagon is a novel investigational orally administered selective agonist of the melanocortin-1 receptor. The drug-drug interaction (DDI) potential of dersimelagon was investigated in both nonclinical (in vitro) and clinical studies. The invitro inhibition of CYP/UGT isoforms and efflux/uptake transporters by dersimelagon was assessed. The impact of 300-mg dersimelagon on the pharmacokinetics (PK) of substrate drugs and the effect of co-administering verapamil on 100-mg dersimelagon PK (as substrate drug) were investigated in healthy participants in a Phase 1 study. DDIs were assessed based on ratios of Cmax and AUC0-∞ of substrate drug administered alone and with dersimelagon (or verapamil). Relatively potent invitro inhibition of CYP2C9, CYP3A, UGT1A1, BCRP, P-gp, and OATPs by dersimelagon was observed. In the clinical study, exposures of atorvastatin (CYP3A, P-gp, BCRP, OATP substrate) rosuvastatin (BCRP and OATP substrate), and β-hydroxy simvastatin (metabolite of simvastatin) increased 2- to 3-fold (atorvastatin: Cmax LS mean ratio = 198.0%; AUC0-∞ ratio = 196.6%; rosuvastatin: Cmax ratio = 316.5%, AUC0-∞ ratio = 206.0%) when co-administered with dersimelagon. Midazolam (CYP3A substrate), digoxin (P-gp), pravastatin (OATP), and simvastatin (CYP3A) did not show any clinically relevant DDI effects when co-administered with dersimelagon. Dersimelagon exposure increased ~25% when co-administered with verapamil, an effect not considered clinically relevant. Dersimelagon 300 mg did not elicit major DDIs involving CYP/UGT enzymes and drug transporters; however, dersimelagon may have potential for clinically relevant DDIs with drugs that are substrates for BCRP, such as atorvastatin and rosuvastatin, and caution should be exercised when co-administering 300-mg dersimelagon with these statin drugs. Trial Registration: ClinicalTrials.gov: NCT04793295, NCT04402489, NCT04440592, NCT02834442, NCT03520036, NCT03503266.

The integration of copper(I)-catalyzed three-component coupling with gold(I)-mediated 6-endo cyclization streamlines the rapid and modular assembly of the substructure of bis-tetrahydroisoquinoline (THIQ) alkaloids. The design of the key synthetic intermediate bearing a 2,3-diaminobenzofuran moiety allows both gold(I)-mediated regiocontrolled 6-endo hydroamination and temporary protection of nitrile and phenolic hydroxy groups. The synthetic strategy enabled the efficient synthesis of the substructure of saframycins bearing isoquinoline and THIQ units in just four steps from the modular assembly of the three components. We also found the unexpected involvement of a fluorescent intermediate in the cascade synthetic process.

Abstract Encapsulation of a single protein within a confined space can lead to distinct properties compared to bulk solutions, but controlling the number of encapsulated proteins and their environment remains challenging. This study demonstrates the encapsulation of single proteins within well‐defined, tunable cavities of self‐assembled coordination cages, thereby enhancing protein stability. Within uniform cavities of size‐tunable coordination cages, 15 different proteins of varying sizes (3–6 nm in diameter) and properties (e.g., isoelectric points and hydrophobicity) were successfully confined. Various analytical techniques confirmed that the proteins maintained their secondary structures and enzymatic activities under denaturing conditions such as exposure to organic solvents, heat, and buffers. These findings suggest that such coordination cages have the potential to serve as synthetic hosts for precisely controlling protein functions within their customizable cavities.

Dersimelagon is a novel, investigational, orally administered, selective agonist of the melanocortin-1 receptor that has demonstrated efficacy at increasing symptom-free light exposure and an acceptable safety profile in patients with protoporphyria. A phase 1 drug-drug interaction (DDI) study demonstrated that dersimelagon 300 mg has the potential for clinically relevant DDIs with drugs that are substrates for breast cancer resistance protein, such as atorvastatin and rosuvastatin. This study uses physiologically based pharmacokinetic (PBPK) modelling to further investigate the DDI effects at lower doses of dersimelagon with substrate drugs. The data from in silico, in vitro and in vivo studies were used to construct a PBPK model for dersimelagon to assess the DDI potential between dersimelagon and substrate drugs for cytochrome P450 3A, P-glycoprotein, organic anion transporting polypeptide 1B1/1B3, organic anion transporter 3 and breast cancer resistance protein, including atorvastatin and rosuvastatin. The systemic exposure of atorvastatin based on the maximum plasma concentration and area under the plasma concentration-time curve was predicted to increase 1.21-fold and 1.25-fold, respectively, if coadministered with dersimelagon 100 mg, and 1.42-fold and 1.45-fold with dersimelagon 200 mg. The systemic exposure of rosuvastatin followed trends similar to atorvastatin (1.67-fold and 1.34-fold increase in maximum plasma concentration and area under the plasma concentration-time curve, respectively, with dersimelagon 100 mg, and 2.40-fold and 1.69-fold with dersimelagon 200 mg). Overall, PBPK modelling results indicate that the simulated changes in plasma exposure of atorvastatin and rosuvastatin following coadministration with dersimelagon 100 or 200 mg are not clinically significant, but caution and appropriate clinical monitoring should be recommended.

Although the use of application (app)s and wearable devices supporting diabetes treatment has spread rapidly in recent years, evidence of their impact, especially in combination of them, is limited. TOMOCO™ is a lifestyle improvement support app that features interactive virtual conversations according to the programmed algorithm guiding users toward their goals of lifestyle improvement. We hypothesized that TOMOCO™ in combination with Fitbit, which accurately tracks users' activity level, would encourage people with type 2 diabetes mellitus (T2DM) to change their lifestyles and improve their glycated hemoglobin (HbA1c) levels without changes in conventional therapy. Thus, we performed the present study to explore the effectiveness of this combination in Japanese participants with T2DM who had not achieved their glycemic targets. In this single-arm exploratory study, participants with T2DM used the TOMOCO™ and Fitbit in addition to the conventional diet/exercise therapy and anti-diabetic drug for 12weeks. They were provided with feedback/advice by health care providers based on the TOMOCO™ and Fitbit records. The primary endpoint was the change in HbA1c from baseline to the end of the observation period. Data were expressed as mean ± standard deviation. Fifty-nine (96.7%) of the 61 participants (male, 42 [71.2%]; age, 60.1 ± 8.7years; HbA1c level, 7.48 ± 0.37% at screening) completed the study. At the end of the observation period, the HbA1c was significantly reduced (- 0.41 ± 0.41%, p < 0.001). This trend was consistent across the preselected patient characteristics, including sex, age, and body mass index. However, it was more pronounced in the participants with earlier stages of behavioral changes defined by the transtheoretical model at baseline. The unique features of TOMOCO™ in combination with Fitbit, together with conventional therapy, may promote a healthy lifestyle and thus contribute to improving HbA1c in people with T2DM. jRCT1070220007.