Clinical Development of Histamine H4 Receptor Antagonists

Abstract

The discovery of the histamine H receptor (HR) provided a new avenue for the exploration of the physiological role of histamine, as well as providing a new drug target for the development of novel antihistamines. The first step in this process was the identification of selective antagonists to help unravel the pharmacology of the HR relative to other histamine receptors. The discovery of the selective HR antagonist JNJ 7777120 was vital for showing a role for the HR in inflammation and pruritus. While this compound has been very successful as a tool for understanding the function of the receptor, it has drawbacks, including a short in vivo half-life and hypoadrenocorticism toxicity in rats and dogs, that prevented advancing it into clinical studies. Further research let to the discovery of JNJ 39758979, which, similar to JNJ 7777120, was a potent and selective HR antagonist and showed anti-inflammatory and anti-pruritic activity preclinically. JNJ 39758979 advanced into human clinical studies and showed efficacy in reducing experimental pruritus and in patients with atopic dermatitis. However, development of this compound was terminated due to the occurrence of drug-induced agranulocytosis. This was overcome by developing another HR antagonist with a different chemical structure, toreforant, that does not appear to have this side effect. Toreforant has been tested in clinical studies in patients with rheumatoid arthritis, asthma, or psoriasis. In conclusions there have been many HR antagonists reported in the literature, but only a few have been studied in humans underscoring the difficulty in finding ligands with all of the properties necessary for testing in the clinic. Nevertheless, the clinical data to date suggests that HR antagonists can be beneficial in treating atopic dermatitis and pruritus.

Histamine-4 receptor antagonist JNJ7777120 inhibits pro-inflammatory microglia and prevents the progression of Parkinson-like pathology and behaviour in a rat model

“…H4R antagonists have proven to be effective in several preclinical models of human diseases including asthma, LPS-induced inflammation, dermatitis, collagen-induced arthritis, neuropathic pain (Hsieh et al, 2010), colitis and histamine-induced pruritus (Thurmond et al, 2008). Based on successful preclinical data, some were translating into clinical trials for pruritus and atopic dermatitis (reviewed in (Thurmond et al, 2008, Thurmond et al, 2017). However, very limited no information is available on the ability of H4R antagonists to treat neurological disorders such as PD.…”

Enigmatic Histamine Receptor H4 for Potential Treatment of Multiple Inflammatory, Autoimmune, and Related Diseases

“…The vast body of accumulating knowledge on physiological and pathophysiological functions associated with H 4 R modulation can be exploited for therapeutic purposes [11]. The properties of H 4 R make this amine receptor and its ligands of interest to specialists in the field of allergology, neurobiology, gastroenterology, endocrinology, and also to researchers of cardiovascular functions [6,50]. The results of research on the role of H 4 R in various pathophysiological and immunological processes indicate its association with the development and course of many diseases including a crucial role of H 4 R in airway and dermal inflammation (Figure 3), pruritus, ocular inflammation, arthritis, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, gastric ulcer, cancer, and pain [12,51].…”

“…Preclinical and clinical data strongly suggest the regulatory involvement of H 4 R in the calcium influx and cellular chemotaxis [53,54], hence establishing a link between the potential therapeutic application of selectively acting H 4 R ligands to inflammatory conditions while also indicating involvement of H 4 R in diseases accompanied by itch and pain [55]. The investigations of histamine in the inflammation process have led to a development of the first highly potent and selective non-imidazole H 4 R antagonist JNJ7777120, followed by reexamination and synthesis of a plethora of H 4 R-targeted compounds [50,51].…”

Homogeneous, Real-Time NanoBRET Binding Assays for the Histamine H3 and H4 Receptors on Living Cells

“…The histamine H 4 receptor (H 4 R) is predominantly expressed on immune cells and linked to inflammatory disorders, such as psoriasis, atopic dermatitis, asthma, and arthritis (Novak et al, 2012;Verweij et al, 2017). In 2016, the first H 3 R-targeting therapeutic, pitolisant (Wakix, Bioprojet Pharma, Paris, France), was approved by the European Medicine Agency for the treatment of narcolepsy (Kollb-Sielecka et al, 2017), whereas H 4 R-targeting drug candidates are in clinical trials for the treatment of various inflammatory disorders (Thurmond, 2015;Attali et al, 2016;Thurmond et al, 2017).…”