In our pursuit of developing a novel and potent potassium-competitive acid blocker (P-CAB), we synthesized pyrrole derivatives focusing on compounds with low log D and high ligand-lipophilicity efficiency (LLE) values. Among the compounds synthesized, the compound 13e exhibited potent H(+),K(+)-ATPase inhibitory activity and potent gastric acid secretion inhibitory action in vivo. Its maximum efficacy was more potent and its duration of action was much longer than those of proton pump inhibitors (PPIs). Therefore, compound 13e (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate, TAK-438) was selected as a drug candidate for the treatment of gastroesophageal reflux disease (GERD), peptic ulcer, and other acid-related diseases.

Studies on the inhibition mechanism of acetogenins, the most potent inhibitors of complex I, are useful to elucidate the structural and functional features of the terminal electron-transfer step of this enzyme. We synthesized acetogenin mimics that possess two alkyl tails without a gamma-lactone ring, named Deltalac-acetogenin, and examined their inhibitory action on bovine heart mitochondrial complex I. Unexpectedly, the Deltalac-acetogenin carrying two n-undecanyl groups (compound 3) elicited very potent inhibition comparable to that of bullatacin. The inhibitory potency of compound 3 markedly decreased with shortening the length of either or both alkyl tails, indicating that symmetric as well as hydrophobic properties of the inhibitor are important for the inhibition. Both acetylation and deoxygenation of either or both of two OH groups adjacent to the tetrahydrofuran (THF) rings resulted in a significant decrease in inhibitory potency. These structural dependencies of the inhibitory action of Deltalac-acetogenins are in marked contrast to those of ordinary acetogenins. Double-inhibitor titration of steady-state complex I activity showed that inhibition of compound 3 and bullatacin are not additive, though the inhibition site of both inhibitors is downstream of iron-sulfur cluster N2. Our results indicate that the mode of inhibitory action of Deltalac-acetogenins differs from that of ordinary acetogenins. Therefore, Deltalac-acetogenins can be regarded as a novel type of inhibitor acting on the terminal electron-transfer step of complex I.

With the aim of developing an improved strategy for the preparation of ethylene-bridged polysilsesquioxanes as thermal insulator materials, this paper describes the synthesis of a crack- and shrinkage-free ethylene-bridged polysilsesquioxane film by the hydrosilylation reaction of hydrodimethyl-silylated oligomethylsilsesquioxane (MSQ-SiH) and dimethylvinyl-silylated oligomethylsilsesquioxane (MSQ-SiVi) in the presence of Karstedt’s catalyst. Polysilsesquioxane precursors were prepared by the sol–gel reaction of triethoxymethylsilane and the successive capping reaction with chlorodimethylsilane and chlorodimethylvinylsilane. The obtained ethylene-bridged polysilsesquioxane film showed lower density and thermal diffusivity (1.13 g/cm3 and 1.15 × 10–7 m2/s, respectively) than a polymethylsilsesquioxane film (1.34 g/cm3 and 1.36 × 10–7 m2/s, respectively). As a result of the introduction of the SiCCSi ethylene bridge, the thermal insulation property of the polysilsesquioxane film was enhanced.

The hybrid antifogging materials poly­(3-aminopropyl)­silsesquioxane (PAPS) and poly­(3-(2-aminoethylaminopropyl)­silsesquioxane) (PAEAPS) were prepared by sol–gel reactions that are autocatalyzed by the amine moieties of the monomers. PAPS and PAEAPS show good film-forming abilities, and the films obtained were found to be uniform and pinhole-free. X-ray diffraction analysis of PAPS and PAEAPS films indicated the formation of ladder-like structures. The PAPS and PAEAPS films exhibit high water uptakes of 34 and 42%, which are 1.2 and 1.5 times that of the typical antifogging polymer poly­(vinyl alcohol) (PVA), respectively. Furthermore, the PAEAPS film exhibits a scratch resistance 4–6 times that of PVA, and a glass substrate bearing a PAEAPS film remained transparent after removal from a refrigerator. Thus, PAEAPS films exhibit high transparency under humidified conditions and show good antifogging ability.

We have synthesized ∆lac-acetogenins that are new acetogenin mimics possessing two n-alkyl tails without an R, -unsaturated γ-lactone ring and suggested that their inhibition mechanism may be different from that of common acetogenins [Hamada et al. (2004) Biochemistry 43, 3651-3658]. To elucidate the inhibition mechanism of ∆lac-acetogenins in more detail, we carried out wide structural modifications of original ∆lac-acetogenins and characterized the inhibitory action with bovine heart mitochondrial complex I. In contrast to common acetogenins, both the presence of adjacent bis-THF rings and the stereochemistry around the hydroxylated bis-THF rings are important structural factors required for potent inhibition. The inhibitory potency of a derivative possessing an n-butylphenyl ether structure (compound 7) appeared to be superior to that of the original ∆lac-acetogenins and equivalent to that of bullatacin, one of the most potent natural acetogenins. Double-inhibitor titration of steady-state complex I activity showed that the extent of inhibition of compound 7 and bullatacin is not additive, suggesting that the binding sites of the two inhibitors are not identical. Competition tests using a fluorescent ligand indicated that the binding site of compound 7 does not overlap with that of other complex I inhibitors. The effects of compound 7 on superoxide production from complex I are also different from those of other complex I inhibitors. Our results clearly demonstrate that ∆lac-acetogenins are a novel type of inhibitor acting at the terminal electron-transfer step of bovine complex I.

G-protein-coupled receptor 52 (GPR52) is an orphan Gs-coupled G-protein-coupled receptor. GPR52 inhibits dopamine D2 receptor signaling and activates dopamine D1/N-methyl-d-aspartate receptors via intracellular cAMP accumulation, and therefore, GPR52 agonists may have potential as a novel class of antipsychotics. A series of GPR52 agonists with a bicyclic core was designed to fix the conformation of the phenethyl ether moiety of compounds 2a and 2b. 3-[2-(3-Chloro-5-fluorobenzyl)-1-benzothiophen-7-yl]-N-(2-methoxyethyl)benzamide 7m showed potent activity (pEC50 = 7.53 ± 0.08) and good pharmacokinetic properties. Compound 7m significantly suppressed methamphetamine-induced hyperactivity in mice after oral administration of 3 mg/kg without disturbance of motor function.

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In the field of organic/inorganic hybrid polymers with the application as thermal insulating materials, ethylene-bridged polysilsesquioxane films are promising materials with enhanced thermal insulating properties due to the presence of intramolecular void spaces in their frameworks. With the aim of increasing the content in intramolecular void spaces to further enhance the thermal property of the resulting material, this paper describes the hydrosilylation reaction of hydrodimethyl-silylated oligomethylsilsesquioxane (MSQ-SiH) and octavinyl polyhedral oligomeric silsesquioxane (Vinyl-POSS) to produce a hybrid film with intramolecular void spaces, which was colorless and transparent due to the formation of covalent SiCCSi bonds. As a control experiment, a polymethylsilsesquixane (MSQ) film and an MSQ film containing 5 wt % of Vinyl-POSS (composite film-5) were prepared. Hybrid film-5 (prepared from MSQ-SiH and 5 wt % of Vinyl-POSS) exhibited lower density and thermal diffusivity (1.19 g/cm 3 and 1.21 × 10 −7 m 2 /s) than the MSQ film (1.34 g/cm 3 and 1.36 × 10 −7 m 2 /s) and composite film-5 (1.37 g/cm 3 and 1.58 × 10 −7 m 2 / s). Hybrid film-5 showed a 5% weight loss temperature (T d 5) and a 10% weight loss temperature (T d 10 ) of 382 and 453 °C, respectively, which were lower than those of the MSQ film (T d 5 of 436 °C and T d 10 of 481 °C) and higher than those of composite film-5 (T d 5 of 325 °C and T d 10 of 453 °C). Positron annihilation lifetime technique revealed that the hole volumes estimated from the value of the positronium lifetime component decreased in the order hybrid film-5 > MSQ film > composite film-5. Taken together, the results demonstrate that the thermal insulating property of the polysilsesquioxane film was improved by the formation of intramolecular void spaces around the POSS molecules.