Association between Skin Carotenoid Levels and Cognitive Impairment Screened by Mini-Cog in Patients with Glaucoma.

Carotenoids, having strong antioxidant properties, have been associated with neurodegenerative conditions like dementia and glaucoma, characterized by neuronal loss leading to cognitive and visual dysfunction. Therefore, carotenoids have attracted attention as factors predictive of the onset and progression of these neurodegenerative diseases. However, the impact of carotenoids on cognitive impairment and glaucomatous visual field defects remains unexplored. We conducted a retrospective, observational clinical study to investigate the association between skin carotenoid (SC) levels and cognitive impairment, as screened by the Mini-Cog test, in glaucoma patients. The study included 406 participants and 812 eyes were examined (average age: 69.7 ± 11.4 years; 228 men, 178 women) with various types of glaucoma: primary open angle (57.6%), exfoliation (18.6%), and other types (23.8%). SC levels were estimated via pressure-mediated reflection spectroscopy. Mixed-effects regression models were utilized to examine the relationship between SC levels, visual field defects, and Mini-Cog results. Of the participants, 28 (6.9%) tested positive on the Mini-Cog, suggesting cognitive impairment. The average SC level in the Mini-Cog positive group was significantly lower than in the negative group (269.5 ± 86.4 A.U. vs. 329.2 ± 120.4 A.U., respectively; p = 0.01). Additionally, the visual field mean deviation (MD) in the Mini-Cog positive group was notably worse than that in the negative group (-19.64 ± 9.07 dB vs. -12.46 ± 9.28 dB, respectively; p < 0.0001). The mixed-effects regression analysis revealed a significant association between Mini-Cog positivity and lower SC levels (p = 0.0006), although SC levels did not significantly correlate with MD (p = 0.3). Our findings suggest that cognitive impairment in glaucoma patients is associated with lower SC levels, underscoring the potential benefits of maintaining carotenoid levels to slow cognitive function decline. The protective role of carotenoids in glaucoma merits further investigation.

Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety.

We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-á-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.

Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor.

Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.

Enhanced Structural Variety of Nonplanar N-Oxyl Radical Catalysts and Their Application to the Aerobic Oxidation of Benzylic C-H Bonds.

The design and synthesis of structurally variable, nonplanar N-oxyl radical catalysts and their application to the aerobic oxidation, etherification, and acetoamidation of benzylic C-H bonds are described. The catalytic oxidation of C-H bonds represents a powerful tool to synthesize oxygenated functional molecules from simple hydrocarbons in a straightforward way. Electron-deficient N-oxyl radical catalysts, such as phthalimidoyl N-oxyl (PINO) radical, generated from N-hydroxyphthalimide (1), have attracted much attention because of their applications in the oxidation of C-H bonds with high bond dissociation energy (BDE). However, a few sites in 1 are available for structural modifications and improvements of the catalytic performance. By replacing one carbonyl group in 1 with a trifluoromethyl (CF3)-substituted sp(3)-carbon, we generated an additional tunable site and a nonplanar backbone, while retaining the desirable electron-withdrawing properties and increasing the lipophilicity with respect to 1. We synthesized a variety of N-hydroxy precatalysts containing such a CF3 moiety, and investigated their utility in the aerobic oxidation of benzylic C-H bonds. Precatalysts with electron-withdrawing substituents, such as trifluoroethoxy and the acetophenone moieties, afforded higher yields than a corresponding methoxy-substituted analogue. The introduction of substituents at the aromatic ring was also effective, as evident from the performance of 7-CF3 and 4,5,6,7-tetrafluoro precatalysts. Especially the combination of trifluoroethoxy- and 4,5,6,7-tetrafluoro substitution afforded a superior performance. These catalyst systems exhibited high functional group tolerance during the aerobic oxidation of C-H bonds, and benzylic etherification and Ritter-type reactions could be carried out at room temperature when a selected precatalyst and N-bromosuccinimide (NBS) were used.

Association Analysis between Cognitive Function Score and Inner Macular Thickness/Visual Field Sensitivity in Glaucoma Patients.

(1) Background: Previous research has investigated the relationship between cognitive impairment, optical coherence tomography (OCT), visual fields (VF), and VF reliability in smaller patient samples using various cognitive assessment tools. This study analyzed the relationship between cognitive function scores using the Mini-Cog test and inner macular thickness (IMT) and VF sensitivity in glaucoma patients. (2) Methods: A retrospective analysis was conducted on 984 patients with 1897 eyes. Assessments included age, sex, intraocular pressure (IOP), and Mini-Cog test scores. Abnormal Mini-Cog scores were observed in 89 patients (9%). Using a mixed-effects model adjusted for background factors, the association between Mini-Cog scores and IMT, parafoveal (PF)-IMT, mean deviation (MD), pattern standard deviation, fixation losses (FL), false negatives (FN), and false positives (FP) was analyzed. (3) Results: Abnormal Mini-Cog scores (≤2) were associated with thinning of the IMT and PF-IMT, worse MDs, and higher FN and FP rates but not with PSD or FL. (4) Conclusions: Glaucoma patients with low cognitive function scores exhibited more advanced glaucoma-related changes in VF testing and morphological tests. Further longitudinal studies are needed to explore the relationship between glaucoma and cognitive impairment.

Intraocular Pressure Changes in Non-Surgical Eyes of Patients Admitted for Glaucoma Surgery.

(1) Background: In glaucoma patients, it is observed that intraocular pressure (IOP) in non-surgical eyes decreases during hospitalization, but detailed data have not been reported. This study aimed to examine changes in IOP in the non-surgical eyes of patients admitted for glaucoma surgery. (2) Methods: This retrospective study included 487 patients (254 males, 233 females). Statistical analysis was performed separately for groups that were and were not under medication treatment. (3) Results: In non-surgical eyes, the difference in IOP between admission and discharge was -1.6 ± 4.8 mmHg (95% confidence interval (CI), -2.1 to -1.2; p < 0.0001) with a significant decrease in the medication group (n = 414), while it was -0.6 ± 4.8 mmHg with no significant change observed (95% confidence interval (CI), -1.7 to 0.57; p = 0.33) in the non-medication group (n = 73). Multiple regression analysis of the medication group showed that IOP at admission (p < 0.0001) and older age (p = 0.03) were associated with the reduction or the rate of reduction in IOP. (4) Conclusions: IOP in the non-surgical eyes of patients admitted for glaucoma surgery with medication decreased during hospitalization. The reduction was more pronounced in individuals with higher IOP at admission and in older patients. It is possible that improved medication adherence contributes to the lowering of IOP.

Exploring Cognitive Impairments Associated with Primary Open-Angle Glaucoma and Exfoliation Glaucoma.

This study explored the link between different types of glaucoma and cognitive function in a cohort of 620 Japanese patients. Participants were categorized into primary open-angle glaucoma (PG), exfoliation glaucoma (EG), and non-glaucomatous control groups. The findings revealed a significant decline in cognitive function as indicated by the Mini-Cog test in the EG group (mean ± SD: 4.0 ± 1, 95% CI: 3.9 to 4.2) compared to the PG group (4.4 ± 0.1, 4.3 to 4.5, p < 0.0001). Levels of fingertip measured advanced glycation end-products (AGEs) were significantly higher in the EG group (mean ± SD: 0.45 ± 0.006, 95% CI: 0.44 to 0.46) compared to the PG group (0.43 ± 0.004, 0.42 to 0.44, p = 0.0014). Although the multivariate analysis initially showed no direct association between glaucoma types and Mini-Cog scores, the EG group exhibited higher age and intraocular pressure (IOP) compared to the PG group. Further analysis revealed that high levels of AGEs were associated with cognitive decline and decreased mean visual fields in the EG group. Age was identified as a cofounding factor in these associations. An inverse correlation was observed between the accumulation of AGEs and skin carotenoid levels. Early detection of cognitive decline in glaucoma patients could enable timely intervention to preserve visual fields. Fingertip measurements of skin carotenoids and AGEs offer promising potential as non-invasive, straightforward diagnostic tools that could be widely adopted for monitoring ophthalmic and cognitive health in glaucoma patients.

Relevance of Diabetic Retinopathy with AGEs and Carotenoid Levels Assessed by Skin Sensors.

Advanced glycation end products (AGEs) and carotenoids, the major prooxidants and antioxidants in vivo, respectively, are thought to be associated with diabetes mellitus (DM). To estimate AGEs and carotenoid levels simultaneously in patients with DM, we used noninvasive fingertip skin sensors. The study population included 249 eyes of 249 Japanese subjects (130 men, 119 women; mean age ± standard deviation, 69.9 ± 12.0 years). Ninety-three patients had DM, which included diabetic retinopathy (DR) (n = 44) and no DR (NDR) (n = 49), and 156 controls. Compared to the controls (0.44 ± 0.07 arbitrary unit (A.U.)), the AGEs scores were significantly higher in DM (0.47 ± 0.09, p = 0.029) and DR (0.49 ± 0.08, p = 0.0006) patients; no difference was seen between NDR (0.45 ± 0.09, p = 0.83) and controls. Multivariate analyses indicated that a higher AGEs level is a risk factor for DR (r = 0.030, p = 0.0025). However, the carotenoid scores did not differ in any comparisons between the controls (327.7 ± 137.0 O.D.) and patients with DM (324.7 ± 126.4, p = 0.86), NDR (320.4 ± 123.6, p = 0.93), or DR (329.4 ± 130.8, p = 0.93). The carotenoid scores correlated negatively with the AGEs scores (r = −0.21, p = 0.0007), and reflected the Veggie intake score (p < 0.0001). In patients with DM, estimations of AGEs and carotenoid levels using skin sensors can be useful for assessing their risk of DR and vegetable intake, respectively.

Fingertip-Measured Skin Carotenoids and Advanced Glycation End Product Levels in Glaucoma.

Carotenoids have antioxidant properties, and the accumulation of advanced glycation end products (AGEs) is associated with reactive oxygen species production; they have attracted attention as factors predictive of the onset and progression in glaucoma. Fingertip measurement is applicable for carotenoids and AGEs due to its noninvasiveness and simplicity. The study included 663 eyes of 663 Japanese subjects (357 males, 306 females). The mean age was 69.9 years with a standard deviation of 11.0. The study population comprised participants with primary open-angle glaucoma (PG) (n = 358), exfoliation glaucoma (EG) (n = 168), and controls (n = 137). Multivariate models suggested that lower skin carotenoid (SC) levels were associated with male gender (standard ß = −0.14), AGE scores (−0.24), and a history of intraocular surgery (−0.22). Higher SC levels were associated with higher vegetable intake scores (0.21 for score 3) and diabetes (0.10). However, no association was seen between SCs and glaucoma type. AGEs levels were negatively associated with carotenoid scores (−0.25), PG (−0.15), and smoking habits (−0.26) and positively correlated with EG (0.14). SCs and AGEs were negatively correlated in the single regression analysis (r = −0.20, p < 0.0001). In conclusion, higher levels of AGEs may be candidates for systemic biomarkers of glaucoma associated with the exfoliation syndrome. SC levels can reflect self-reported daily vegetable intake.

Potassium carbonate-promoted stereospecific 5-endo-trig cyclization of unactivated allenes in the absence of any transition metals.

Formation of 3-pyrrolines from simple unactivated allenes bearing a protected amino group under basic conditions is described. Treatment of alpha-amino allenes with potassium carbonate in DMF under reflux in the absence of any transition-metal catalysts gave the corresponding 3-pyrrolines in good to excellent yields, by 5-endo-trig mode cycloisomerization. The reaction of internal allenes with an axial chirality afforded the corresponding 3-pyrrolines in a stereoselective manner.

Novel synthesis of 3-azabicyclo[3.1.0]hexanes by unusual palladium(0)-catalyzed cyclopropanation of allenenes.

Novel stereoselective synthesis of 3-azabicyclo[3.1.0]hexanes from allenenes is presented. Treatment of N-protected 4-alkyl-4-(N-allyl)amino allenes with allyl carbonate and a catalytic amount of Pd(2)(dba)(3).CHCl(3) in MeCN leads to stereoselective formation of the 3-azabicyclo[3.1.0]hexane framework in moderate to good yields. [reaction: see text]

A highly regio- and stereoselective formation of bicyclo[4.2.0]oct-5-ene derivatives through thermal intramolecular [2 + 2] cycloaddition of allenes.

Thermal [2 + 2] cycloaddition of allenes with an additional multiple bond is described. By simply heating the allenenes or allenynes having a three-atom tether in an appropriate solvent such as dioxane or DMF, the distal double bond of the allenic moiety regioselectively participates in the cycloaddition to form bicyclo[4.2.0]oct-5-ene derivatives in good to excellent yields. In all the reactions of allenenes, the olefin geometry was completely transferred to the cycloadducts. While the reaction of terminal allenes afforded bicyclic cyclobutane derivatives as a single isomer, the cycloaddition of some internal allenes with axial chirality yielded a diastereomeric mixture of cycloadducts. These results are in good accordance with the stepwise mechanism through a biradical intermediate with a coplanar allyl radical.

Palladium(0)-catalyzed tandem cyclization of allenenes: direct construction of tricyclic heterocycles through aromatic C--H activation.

Palladium(0)-catalyzed tandem cyclization of allenenes is described. Treatment of allenenes with an aryl halide, potassium carbonate, and catalytic [Pd(PPh(3))(4)] in dioxane afforded tri- or tetracyclic heterocycles in moderate to good yields through insertion of arylpalladium(II) halide into the allenic moiety, intramolecular carbopalladation, and aromatic C--H bond activation. The substituent on the olefin terminus has proven to be essential for the success of the tandem cyclization. The reaction with heterocyclic aryl halides such as iodopyrazine or 4-bromo-1-methylindole afforded tri- or tetracyclic heteroaromatic products in good yields.

Palladium(0)-catalyzed stereoselective cyclization of allenenes: divergent synthesis of pyrrolidines and 3-azabicyclo[3.1.0]hexanes from single allenenes.

Two novel palladium(0)-catalyzed cyclizations of allenenes are described. Treatment of allenenes such as N-(1-alkyl-2,3-butadienyl)-N-allylsulfonamide with an aryl halide and K(2)CO(3) in the presence of a catalytic amount of Pd(PPh(3))(4) in dioxane affords 2,3-cis-pyrrolidines in a stereoselective manner. In sharp contrast, cyclization of the same allenenes using catalytic Pd(2)(dba)(3) x CHCl(3) in the presence of allyl methyl carbonate in CH(3)CN leads to stereoselective formation of a 3-azabicyclo[3.1.0]hexane framework in moderate yields.