Sachie Arai

Synthesis of J-113397, the first potent and selective ORL1 antagonist

Abstract The first potent and selective small molecule ORL1 antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) was synthesized. J-113397 is the only available potent and selective ORL1 antagonist, which is a very useful pharmacological tool for elucidating the physiological roles of the nociceptin–ORL1 system. J-113397 was synthesized from ethyl 4-oxo-3-piperidinecarboxylate and a coupling reaction of 2-fluorobenzene with 4-amino-ethoxycarbonylpiperidine is a key step.

STEREOSELECTIVE SYNTHESIS OF J-104,118 AND J-104,123, NOVEL, POTENT INHIBITORS OF SQUALENE SYNTHASE

Abstract A novel class of squalene synthase inhibitors (J-104,118 and J-104,123) were synthesized efficiently. An amine intermediate 1 was synthesized using two distinct methods. First, the racemic amine 1 was synthesized diastereoselectively using a key reaction consisting of the stereo-controlled reduction of the ketone 7 by L-Selectride®. Second, the optically active amine 1 was synthesized efficiently and enantioselectively using Sharpless dihydroxylation as a key reaction. A stereo-controlled method for synthesizing J-104,123 was developed starting from a commercially available methyl ( R )-3-hydroxybutyrate.