“Magic Chloro”: Profound Effects of the Chlorine Atom in Drug Discovery

Chlorine is one of the most common atoms present in small-molecule drugs beyond carbon, hydrogen, nitrogen, and oxygen. There are currently more than 250 FDA-approved chlorine-containing drugs, yet the beneficial effect of the chloro substituent has not yet been reviewed. The seemingly simple substitution of a hydrogen atom (R = H) with a chlorine atom (R = Cl) can result in remarkable improvements in potency of up to 100,000-fold and can lead to profound effects on pharmacokinetic parameters including clearance, half-life, and drug exposure in vivo. Following the literature terminology of the "magic methyl effect" in drugs, the term "magic chloro effect" has been coined herein. Although reports of 500-fold or…