Functional Profiling of 2-Aminopyrimidine Histamine H₄ Receptor Modulators

Abstract

Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.

UR-DEBa242: A Py-5-Labeled Fluorescent Multipurpose Probe for Investigations on the Histamine H3 and H4 Receptors

“…[207][208][209][210]245 To improve the translational value of animal models, new molecular tools for the H 4 R are needed, comprising balanced functional profiles across the species with a special emphasis on the most important laboratory animals like mice and rats. With 2,4-diaminopyrimidine-type agonists [246][247][248] (example see Figure 1.5) and antagonists [e.g. JNJ-39758979, (Figure 1.…”

[3H]UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H4 Receptors

“…The human histamine H 4 receptor (hH 4 R) was discovered at the turn of the millennium as the latest member of the histamine receptor family (H 1–4 Rs) − and is expected to be a promising target for the treatment of disorders of the immune system (e.g., rheumatoid arthritis, bronchial asthma). , The expression and a potential physiological role of the H 4 R in the brain was controversially discussed in the literature . For investigations on the (patho)­physiology of the H 4 R, mouse and rat became the most important laboratory animals . However, the pharmacological evaluation of the rodent histamine H 4 receptors (mH 4 R, rH 4 R) is compromised by species-dependent discrepancies regarding the potencies (e.g., 1 , 2 , and 3 ) and/or the quality of action (e.g., 4 , 5, and 6 ) of standard ligands for the hH 4 R (Figure ).…”

A Single Amino Acid Difference between Mouse and Human 5-Lipoxygenase Activating Protein (FLAP) Explains the Speciation and Differential Pharmacology of Novel FLAP Inhibitors

“…Many examples of speciation that have impacted drug discovery efforts exist in the literature and cover a broad range of protein families including G protein-coupled receptors (27), cytochrome P450 isoforms (28), and the MAPEG member microsomal prostaglandin E synthase-1 (29), for example. In the simplest of cases, research teams have identified an appropriate preclinical species, with homologous target protein sequence to human, to enable translational models.…”