The kinetic isotope effect in the search for deuterated drugs.

Abstract

The kinetic isotope effect has long been exploited by physical organic chemists to study reaction mechanisms due to its effect on reaction rates when cleavage of a C-isotope bond is rate determining. Medicinal chemists have also used the deuterium kinetic isotope effect to slow the cytochrome P450 metabolism of the deuterated versions of drug candidates, with the first in vitro microsome studies of deuterated morphine appearing in the literature in the 1960s, and a deuterated alanine compound from Merck going all the way to phase IIb in the 1970s. The recent emergence of companies such as Concert Pharmaceuticals and Auspex Pharmaceuticals, based solely on the idea of deuterium-for-hydrogen versions of existing drugs, has reinvigorated the backers of the deuterium camp, and established the strategy as a viable low-risk approach to drug development. A history of the deuterium kinetic isotope effect is presented, along with examples of deuterated drugs that span 50 years, from 1960 to present day. Specific examples of compounds from the Concert and Auspex pipelines are also analyzed and the pros and cons of their approach are discussed.