Site-selective Deuteration Aimed at Development of Heavy Drugs

Deuterium (D) is a stable and nonradioactive isotope of hydrogen (H), and deuterated compounds have broad applications. Especially, the deuterium kinetic isotope effect, attributed from the higher dissociation energy of the carbon-deuterium (C-D) bond compared with that of carbon-hydrogen (C-H) bond, has attracted considerable attention in recent drug discovery studies. The deuterium switch (replacement of C-H bonds with C-D bonds) at the metabolic sites (the α-position to heteroatoms etc.) of drugs improves the bioavailability of mother drugs (H forms) owing to the deuterium kinetic isotope effect (KIE). Therefore, the development of efficient synthetic method of deuterated drugs (heavy drugs) is eagerly desired. We have recently synthesized the deuterated alkyl reagents (dn-alkyl diphenylsulfonium salts and dn-alkyl thianthrenium salts) aimed at development of heavy drugs, possessing high deuterium contents at the adequate positions. Additionally, photocatalytic site-selective deuteration of α-thio C(sp3)-H bonds and polyethylene glycol derivatives were also successfully accomplished. In this review, we explain the approved heavy drugs and their characters, and our recent results of deuteration are introduced.