There is a large body of evidence suggesting that increased histamine levels in the CNS exert an inhibitory effect on food intake and weight gain that is mediated by the histamine H1 receptors. Furthermore, it is clear that histamine levels in the brain will increase with antagonism of the H3 receptor. Thus H3 antagonists will reduce food intake and reduce weight by elevating brain histamine. Pharmacological evidence showed that the histamine H3 receptor is an autoreceptor that plays a major role controlling the histaminergic tonus in the CNS. A stimulation of the H3 receptor decreases histamine release and histamine synthesis. An H3 receptor antagonist increases histamine synthesis and histamine release.
Experimental data supporting the importance of the histaminergic system in food intake regulation and weight control have recently been the subject of extensive reviews.
In man, there are two lines of indirect evidence that suggest that an increased histaminergic tonus in the CNS will be of relevance in weight control. First, it has been observed that the degree of increase in food intake in rodents treated with tricyclic antidepressants is related to the compounds’ affinities to the H1 receptor. This fact is in agreement with clinical studies in humans and can probably partly explain why treatment with tricyclic antidepressants and atypical antipsychotics often induces excessive body weight gain. Secondly, treatment with antihistamines (histamine H1 receptor antagonists) for allergic conditions can induce unwanted body weight gain in humans.
HPP404 has been identified as a selective H3 receptor antagonist. It is effective in producing sustained reductions of food intake and impressive reductions of body weight in rodent models of obesity.
Treatment with HPP404 in animals has consistently demonstrated a significant reduction in: food intake, cumulative body weight gain, and in total body fat compared and was comparable to the CB1 antagonist, Rimonabant.
HPP404 has completed a 30-day trial in healthy obese subjects where the drug was well tolerated with no CNS related side effects. Despite lack of dietary restrictions a meaningful weight reduction was seen.