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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.
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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.
Assuntos
Descoberta de Drogas , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Pirimidinas/farmacologia , Estilbenos/farmacologia , Animais , Bovinos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Pirimidinas/síntese química , Pirimidinas/química , Estilbenos/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/química , Pirimidinas/química , Pirimidinas/farmacologia , Quinoxalinas/química , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Concentração Inibidora 50 , Simulação de Dinâmica Molecular , Inibidores de Fosfodiesterase/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Pirimidinas/síntese química , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Compostos de Benzil/química , Ftalimidas/química , Aerobiose , Catálise , Radicais Livres/química , Estrutura Molecular , OxirreduçãoRESUMO
(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.
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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.
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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.
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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.
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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]
RESUMO
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.
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Alcadienos/química , Alcinos/química , Compostos Bicíclicos com Pontes/síntese química , Catálise , Ciclização , Paládio/química , Estereoisomerismo , Especificidade por SubstratoRESUMO
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.
Assuntos
Alcenos/síntese química , Hidrocarbonetos Halogenados/química , Compostos Organometálicos/química , Paládio/química , Alcenos/química , Catálise , Ciclização , Hidrocarbonetos Halogenados/síntese química , Estrutura Molecular , EstereoisomerismoRESUMO
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.