Biomedical Engineering Reference
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FIGURE 17.9 Pharmacophore modeling leading to the design of new ligands. Two reference histamine H 4
ligands (VUF6884 and JNJ7777120) were used to construct a pharmacophore model. This model indirectly
describes the histamine H 4 receptor-binding site. Based on this model, novel and potent ligands that i t the
binding pocket could be designed, e.g., VUF10148). Carbon atoms in green, nitrogen atoms in blue, oxygen
atoms in red, and hydrogen atoms in white. Color coding surface: hydrogen-bonding region in purple, hydro-
phobic regions in yellow, and mild polar regions in blue.
a half-life of only 2 h in rats. The subsequently developed benzimidazole derivative JNJ10191584
is also a neutral H 4 a nt agon ist. T h is compou nd is ora l ly act ive in vivo and has improved liver microsomes
stability but still a limited half-life. Also derived from a HTS hit, a series of 2-arylbenzimidazoles
have been described as ligands with low nanomolar afi nity for the H 4 receptor. In addition, rational
approaches like pharmacophore modeling and subsequent ligand design (Figure 17.9) are being used
to develop novel H 4 receptor ligands. Considering the number of H 4 receptor related patent applications
that have recently been disclosed, it can be anticipated that many new H 4 ligands will be described in
scientii c literature in the near future.
17.5.4 T HERAPEUTIC U SE OF H ISTAMINE H 4 R ECEPTOR L IGANDS
The presence of the H 4 receptor on immunocompetent cells and cells of hematopoietic lineage
suggests that this new histamine receptor subtype plays an important role in the immune system.
This hypothesis is supported by the fact that IL-10 and IL-13 modulate H 4 receptor expression and
that binding sites for cytokine-regulated transcription factors, like interferon-stimulated response
element (ISRE), interferon regulatory factor-1 (IRF-1), NF-κB, and nuclear factor-IL6 (NF-L6),
are present upstream of the H 4 gene. Considering the physiological role of the H 4 receptor, several
applications are currently under preclinical investigation, including allergy and asthma, chronic
inl ammations such as inl ammatory bowel disease (IBD) and rheumatoid arthritis. The H 4 receptor
is also being associated with pruritus (itch) and is involved in the progression of colon cancer. At the
moment, therapeutic applications are clearly anticipated for H 4 receptor antagonists (inverse ago-
nists). In view of the strong interests of pharmaceutical industries more evidence for a therapeutic
role of H 4 receptor ligands is soon to be expected.
17.6 CONCLUDING REMARKS
The medicinal chemistry of histamine receptors has so far been a very rewarding arena. Major
blockbuster drugs have been developed on the basis of H 1 and H 2 receptor targeting. Expectations
for ligands targeting the two latest additions to the histamine receptor family are currently also very
high. Interestingly, for each of these receptor subtypes highly selective agonists and antagonists
have been developed. The wide chemical diversity of the various selective receptor ligands rel ects
the relatively low homology between the various receptors (only the H 3 and H 4 receptors resemble
each other to some extent). Moreover, it offers today's medicinal chemists an attractive arena for
highly effective drug discovery efforts. This will be further aided by the recent elucidation of the
x-ray structure of the beta 2 receptor, hopefully allowing future structure-based drug design.
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