Novel Tetrahydroquinazolinamines as Selective Histamine 3 Receptor Antagonists for the Treatment of Obesity

The
histamine 3 receptor (H3R) is a presynaptic receptor, which
modulates several neurotransmitters including histamine and various
essential physiological processes, such as feeding, arousal, cognition,
and pain. The H3R is considered as a drug target for the treatment
of several central nervous system disorders. We have synthesized and
identified a novel series of 4-aryl-6-methyl-5,6,7,8-tetrahydroquinazolinamines
that act as selective H3R antagonists. Among all the synthesized compounds,
in vitro and docking studies suggested that the 4-methoxy-phenyl-substituted
tetrahydroquinazolinamine compound 4c has potent and
selective H3R antagonist activity (IC50 < 0.04 μM).
Compound 4c did not exhibit any activity on the hERG
ion channel and pan-assay interference compounds liability. Pharmacokinetic
studies showed that 4c crosses the blood brain barrier,
and in vivo studies demonstrated that 4c induces anorexia
and weight loss in obese, but not in lean mice. These data reveal
the therapeutic potential of 4c as an anti-obesity candidate
drug via antagonizing the H3R.