Synthesis and evaluation of novel substituted N-(2-phenylbutyl)-5,6,7,8-tetrahydro-quinazolin-4-amines as allosteric modulators of HIV-DAT-tat interaction.

Allosteric modulation of interaction between Dopamine Transporter (DAT) and HIV-1 transactivator of transcription (Tat) by small molecules suggests a potential therapeutic intervention for HIV-infected patients with concurrent cocaine abuse. We have previously reported in vitro and in vivo studies on a novel allosteric modulator, SRI-32743, which was shown to attenuate Tat-induced inhibition of [H]DA uptake and decrease the cocaine-mediated dissociation of [H]WIN35,428 binding in CHO-K1 cells expressing hDAT. Herein we report our initial structure-activity relationship (SAR) studies on SRI-32743 with the goal of identifying more potent analogs with improved absorption, distribution, metabolism, and excretion (ADME) properties, that can evolve into a pre-clinical candidate against HIV-1 associated neurocognitive disorders (HAND). Our investigation led to the discovery of a novel N-(2-phenylbutyl)-5,6,7,8-tetrahydroquinazolin-4-amine 4e (SRI-45949), which exhibited comparable inhibitory potency and improved solubility as compared to SRI-32743.