Comprehensive Analysis: JNJ20190729, a Novel H4 Receptor Antagonist

This report details the research and development of JNJ20190729, a novel H4 receptor antagonist, for the treatment of allergic rhinitis, focusing on the impact of environmental pollution. The study explores the causes and current treatments of allergic rhinitis, including the drawbacks of existing antihistamines. It investigates the H4 receptor as a potential therapeutic target, detailing the screening process of various compounds, including JNJ20190729. The report presents the results of drug testing in animal models, gene expression analysis, and clinical trials, evaluating the efficacy and side effects of the candidate drug. It also includes data from animal models, comparing the efficacy of the drug with other competitor drugs. The report highlights the importance of the animal model and discusses potential side effects observed. Finally, the report concludes with a summary of findings and thoughts on which drug to take forward to human clinical trials, discussing efficacy versus side effects.

Development of
JNJ20190729, a new H4
receptor antagonist for
treatment of Hay fever

Allergic Rhinitis- Causes and Treatment
• Environmental pollution caused by
the air pollutants are the potent
cause of several respiratory
problems.
• Allergic rhinitis commonly known
as hay fever causes inflammation
of the nose due to the reaction of
the immune system to allergens
present in the air (Kakli, H. A., &
Riley, T. D. (2016).
• The common symptoms include
runny nose with clear fluid
discharge from the nasal cavity,
swollen and watery eyes which can
become red and itchy depending on
the severity.
Fig 1: Symptoms of Hay fever
(Independent nursing, 2017)
Fig 2: Onset of the allergy in hay
fever (Independent nursing, 2017)

• The treatment of any allergy involves the use of
antihistamine that targets the cell receptors for
histamine. Histamine is the chemical substance
released by the immune system to combat
allergen attack (Bernstein, D. I., Schwartz, G., &
Bernstein, J. A. (2016). Excessive histamine
induces allergy symptoms.
• The leading manufacturers of anti histamine
drugs include Merck, Pfizer, Novartis, Johnson
and Johnson, Bayer, Astra Zeneca, Akorn, Teva
Pharmaceuticals.
• There are a lot of side effects of using anti
histamines. These include drowsiness, dizziness,
nausea, vomiting, drying of mouth, restlessness,
in adverse conditions it affect the nervous
system as well.
Allergic Rhinitis- Causes and Treatment
Fig 3: Evolution of antihistamines (Simons &
Simons, 2011).

H4 Receptor- A good target
• H4 is the fourth histamine receptor that is exclusively expressed on hematopoietic
cells that promotes the development of the symptoms of allergy as well as asthma
(Liu et al., 2014).
• The H1 receptor antagonists are the mainstay but they fail to show efficacy in
reduction of the allergy symptoms.

Screening of the H4 antagonist
• H4 is a target for allergy and asthma. Hence asthma and allergy can be treated by
targeting the H4 receptor.
• The drugs that were considered for screening had three known antagonists
VUF-6002, JNJ777120 and thioperamide.
• The structurally similar compounds of the antagonist had been retrieved from
PubChem and database was formed. Some compounds that had high docking
scores were retrieved.
• All of the compounds proved to interact with the Asp64 target of the H4 receptor
(Ehling et al., 2016).

Drawbacks of some data obtained
• According to the literature review there has been a lot of H4 receptor antagonists
reported but a very less number amongst them has been studied in humans due to
the hindrance faced in targeting a suitable ligand inclining to all the properties
important for analysis in the clinic.

Screening results of the competitive drugs
The IC50 of the competitor drugs A-940894 and JNJ7777120 is graphically
depicted above (Strakhova et al., 2009).

Drugs that are a potent competitor
• JNJ777120 is used extensively in in vitro cell models and animal models that
concluded that H4 antagonists can have anti inflammatory properties. It can be
considered as a potent competitor.

The animal model selected
• Male rats (Sprague-Dawley) were used as the animal model.
• The animals were acclaimed in the lab for a week before the
onset of the experiment
• They were housed in three with free access to food and
water.
• All efforts were made to fulfil the 3Rs principle of the
ethical values (Dettori et al., 2018)
Sprague-Dawley Rats

• Venous blood was taken from the healthy host inclining to the ethical policies.
• The eosinophil were extracted from the blood and isolated.
• The activity of the drugs were tested after administering various amounts to the
extracted blood.
The animal model selected

Results of the drug testing model
• The H4 antagonist was found to successfully bind to the human as well as rat H4
receptors.
• It showed about 50 fold selective binding for human H4 receptor.
• However, depending on the dosage this antagonist promoted blocking of
histamine evoked calcium responses.
• It also inhibited changes in the shape of the bone marrow induced mast calls.

Results of the drug testing model
The adjoining graphical representation shows that the allergic
symptoms is gradually reduced after administering the candidate
drug (Ebrahim et al., 2018).
AR: Allergic rhinitis
In the photomicrograph Fig A is the normal cells of nasal mucosa
of the rat.
Fig B is the cells that is affected by pollution induced rhinitis.
Fig C: Photomicrograph of nasal mucosa cells that are damaged
due to the severity of the symptoms.
Fig D: Photomicrograph of cells gradually normalising after
administering the candidate drug (Ebrahim et al., 2018).