Discovery of TAK-925 as a Potent, Selective, and Brain-Penetrant Orexin 2 Receptor Agonist.

TAK-925, a potent, selective, and brain-penetrant orexin 2 receptor (OX2R) agonist, [methyl (2,3)-3-((methylsulfonyl)amino)-2-(((-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, ], was identified through the optimization of compound , which was discovered by a high throughput screening (HTS) campaign. Subcutaneous administration of compound produced wake-promoting effects in mice during the sleep phase. Compound (TAK-925) is being developed for the treatment of narcolepsy and other related disorders.

Kinetic resolution of an indan derivative using Bacillus sp. SUI-12: synthesis of a key intermediate of the melatonin receptor agonist TAK-375.

The chiral indan derivative (S)-2 (2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl-amine) was synthesized by enzyme-catalyzed asymmetric hydrolysis of the racemic acetamide 1 (N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]acetamide). The reaction was carried out using Bacillus sp. SUI-12 screened for the ability to hydrolyze 1 to give (S)-2 with high enantioselectivity.

Microbial enantioselective ester hydrolysis for the preparation of optically active 4,1-benzoxazepine-3-acetic acid derivatives as squalene synthase inhibitors.

Microbial enantioselective ester hydrolysis for the preparation of optically active (3R,5S)-(-)-5-phenyl-4,1-benzoxazepine-3-acetic acid derivatives as potent squalene synthase inhibitors was investigated. Pseudomonas diminuta and Pseudomonas taetrolens hydrolyzed the racemic ethyl ester of the 5-(2-chlorophenyl) analogue to yield the (-)-carboxylic acid with excellent enantiomeric excess (>99% ee). We found that the (-)-enantiomer was an active inhibitor.