Identification of a Novel Benzoxazolone Derivative as a Selective, Orally Active 18 kDa Translocator Protein (TSPO) Ligand

Optimization of the pharmacokinetic properties for a series of benzoxazolone derivatives led to the identification of <b>9b</b>, which showed anxiolytic effect in a rat model. However, <b>9b</b>, like known benzodiazepines, induced motor impairment. Investigation into the cause of this unexpected side effect and management of <b>9b</b> off-target binding affinity led to the identification of <b>10d</b>, which showed oral anxiolytic effect in the rat model with improved safety profile

Catalytic Enantioselective Strecker Reaction of Ketoimines

A new method for the catalytic enantioselective Strecker reaction (cyanation) of N-diphenylphosphinoyl ketoimines is described. The asymmetric catalyst is a chiral gadolinium complex prepared from Gd(OiPr)3 and the d-glucose-derived ligand 3 in a 1:2 ratio. The reaction has a broad substrate generality, giving high enantioselectivity from aromatic, ethyl, primary alkyl, and α,β-unsaturated ketoimines. The products could be easily converted to disubstituted α-amino acids and their derivatives

Synthesis and Electrochemistry of Tetraphenylporphyrins Containing an Antimony−Carbon σ-Bond

The following five antimony(V) tetraphenylporphyrins with σ-bonded antimony−carbon bonds were synthesized:  [(TPP)Sb(CH3)2]+PF6-, [(TPP)Sb(OCH3)(OH)]+PF6-, [(TPP)Sb(CH3)(OH)]+ClO4-, [(TPP)Sb(CH3)(OCH3)]+ClO4-, and [(TPP)Sb(CH3)(F)]+PF6-. Each compound is stable toward air and moisture and has a high melting point (>250 °C). The electrochemistry and spectroelectrochemistry of these σ-bonded porphyrins were examined in benzonitrile or dichloromethane containing 0.1 M tetrabutylammonium perchlorate as supporting electrolyte and the data compared to those for three previously synthesized OEP derivatives containing similar σ-bonded and/or anionic axial ligands. Each porphyrin shows two reversible reductions and up to a maximun of one oxidation within the potential window of the solvent. Spectroelectrochemical data indicate formation of a porphyrin π anion radical upon the first reduction as do ESR spectra of the singly reduced species. However, a small amount of the Sb(III) porphyrin products may be generated via a chemical reaction following electron tranfer. An X-ray crystallographic analysis of [(TPP)Sb(CH3)(F)]+PF6- is also presented:  monoclinic, space group C2/c, Z = 8, a = 24.068(5) Å, b = 19.456(4) Å, c = 18.745(3) Å, β = 94.69(2)°, R = 0.056

Switching Enantiofacial Selectivities Using One Chiral Source: Catalytic Enantioselective Synthesis of the Key Intermediate for (20<i>S</i>)-Camptothecin Family by (<i>S</i>)-Selective Cyanosilylation of Ketones

Switching Enantiofacial Selectivities Using One Chiral Source:  Catalytic Enantioselective Synthesis of the Key Intermediate for (20S)-Camptothecin Family by (S)-Selective Cyanosilylation of Ketone

Tricyclic Indole-2-carboxylic Acids: Highly in Vivo Active and Selective Antagonists for the Glycine Binding Site of the NMDA Receptor

A series of tricyclic indole-2-carboxylic acid derivatives were synthesized and evaluated by the radioligand binding assay and the anticonvulsant effects in the mouse NMDA-induced seizure model. Among them, derivatives of 3S-(−)-4 such as 3a, 3f, and 3g which had certain zwitterionic anilides showed high affinity to the NMDA-glycine binding site. The absolute configuration of 3S-(−)-4 was confirmed by X-ray crystallographic analysis. In particular, 3g (SM-31900) was found to be a highly active glycine antagonist for both in vitro and in vivo assays (Ki = 1.0 ± 0.1 nM, ED50 = 2.3 mg/kg, iv) and also showed high selectivity for the glycine site. In addition, 3g was soluble enough in aqueous media (>10 mg/mL at pH 7.4) to use for medications by intravenous injection