A Series ofAryl-Substituted-(biphenyl)methyl-sulfinylmethylthiazolesas Novel and Atypical Dopamine Transporter Inhibitors

Abstract Dependence on psychostimulants, including cocaine and methamphetamine, is driving the fourth wave of U.S. drug overdoses. The search for atypical dopamine transporter (DAT) inhibitors for the treatment of psychostimulant use disorders has identified both structurally and pharmacologically diverse compounds that bind DAT but do not produce cocaine-like behaviors in experimental animals. Nevertheless, low binding affinity at hDAT, metabolic instability and high potency in the human ether-à-go-go-related gene (hERG) channel have limited further development. Herein, we describe the synthesis of a novel series of aryl-substituted-(biphenyl)methyl-sulfinylmethylthiazoles and identify two lead molecules, 32b and 39b that bind hDAT (Ki = 63.0 and 78.5 nM, respectively) and have hERG channel activities predicted to be in the low μM range. Despite demonstrated brain penetrability and target engagement neither compound produced cocaine-like locomotor stimulation or conditioned place preference, in mice, thus representing a new class of atypical DAT inhibitors and potential leads for pharmacotherapeutic development.