Sunday, October 30, 2016

Drugs in Clinical Pipeline: Danirixin | C-X-C Motif Chemokine Receptor 2 (CXCR2) Antagonist | CXCL8 (Interleukin-8) Antagonist | Management of Chronic Obstructive Pulmonary Disease (COPD)

Danirixin [(S)-1-(4-chloro-2-hydroxy-3-(piperidin-3-ylsulfonyl)phenyl)-3-(3-fluoro-2-methylphenyl)urea] is a small, selective and reversible antagonist for C-X-C motif chemokine receptor 2 (CXCR2, Interleukin 8 receptor, beta). It has high affinity for chemokine (C-X-C motif) ligand 8 (CXCL8) with nanomolar potency (IC50 for CXCL8 binding = 12.5 nM). The compound has demonstrated potent antagonism of CXCR2 activity in vitro and anti-inflammatory effects in various preclinical models [1, 2].

Structure of Danirixin. Intramolecular bond is predicted.
Danirixin: 2D and 3D Structure

The pharmacologic activity and duration of action following oral administration supports Danirixin’s potential use as an oral, anti-inflammatory agent in the treatment of disorders associated with the accumulation of neutrophils especially in development for treatment of chronic obstructive pulmonary disease (COPD).

Excessive neutrophil presence and activation is important in a number of acute and chronic inflammatory diseases. The CXCR2 chemokine receptor is important in controlling the extravasation and activation of neutrophils. Selective antagonism of the CXCR2 receptor is a potential approach to reducing neutrophil migration and activation.

The dose-dependent inhibition of agonist-induced neutrophil activation following single and repeated once daily oral administration of Danirixin suggests that this CXCR2 antagonist may have benefit in neutrophil-predominant inflammatory diseases. Danirixin is being evaluated as a potential anti-inflammatory medicine.

Chemokines, Neutrophil and Chronic Obstructive Pulmonary Disease (COPD) :

Chemokines are a family of small cytokines, or signaling proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines. Chemokines have been classified into four main subfamilies: CXC, CC, CX3C and XC. All of these proteins exert their biological effects by interacting with G protein-linked transmembrane receptors called chemokine receptors, which are selectively found on the surfaces of their target cells.

The major role of chemokines is to act as a chemoattractant to guide the migration of cells.  During inflammation chemokines are released from a wide variety of cells in response to bacterial infection, viruses etc. Their release is often stimulated by pro-inflammatory cytokines such as interleukins. Inflammatory chemokines function mainly as chemoattractants for leukocytes, recruiting monocytes, neutrophils and other effector cells from the blood to sites of infection or tissue damage.

CXCR2, one of a family of CXC chemokine receptors, is necessary for the chemokine-mediated recruitment of neutrophils to sites of inflammation. The neutrophil is thought to be an important contributor, via the release of tissue-destructive proteases and other mediators, to excess mucus production, airway stenosis, and destruction of the lung parenchyma which, in part, is responsible for the decline in lung function associated with chronic obstructive pulmonary disease (COPD).

Levels of CXCL8 (interleukin-8) and other CXCR2 ligands (e.g. CXCL5 or ENA-78) are elevated in bronchoalveolar lavage fluid and the sputum of patients with COPD. Selective antagonism of the interaction between the CXCR2 chemokine receptor and its various ligands provides a potential targeted strategy for reducing the underlying inflammation that contributes to the deleterious effects of an excessive neutrophil response.

The potential for CXCR2 antagonism to reduce neutrophil recruitment into the lung has been demonstrated previously in experimental human models of lung inflammation (ozone challenge) and in initial studies in patients with severe asthma and COPD. Transient reductions in blood neutrophils have been observed with small molecule CXCR2 antagonists following short and long term oral administration leading to concerns about a potential impact on host defense and innate immunity, particularly with chronic use. It is therefore desirable to identify a CXCR2 antagonist that would have the intended efficacy in the target tissues without substantially impacting circulating neutrophil counts [1, 2].

Mechanism of Action in Danirixin:

Danirixin is one of the potent 2-hydroxyphenyl ureas CXCR2 inhibitor coming from Glaxo SmithKline pipeline. The compound has demonstrated potent antagonism of CXCR2 activity in vitro and anti-inflammatory effects in various preclinical models.

Danirixin demonstrated a dose-dependent inhibition of CXCL1-induced CD11b expression following single doses between 50 to 200 mg, which was maintained after 14 days of dosing. The optimal extent of pharmacodynamic activity needed is unknown, but it is likely that less than complete inhibition of CXCR2 activity is desirable in order to obtain a balance between clinical benefit, while minimizing the impact on innate immunity and host defense.

Reported Activities for Danirixin:

IC50 for CXCL8 binding = 12.5 nM

Common name: GSK1325756; GSK-1325756; GSK 1325756; Danirixin

Trademarks: -

Molecular Formula: C19H21ClFN3O4S

CAS Registry Number: 954126-98-8

CAS Name: (S)-1-(4-chloro-2-hydroxy-3-(piperidin-3-ylsulfonyl)phenyl)-3-(3-fluoro-2-methylphenyl)urea

Molecular Weight: 441.90



InChI: InChI=1S/C19H21ClFN3O4S/c1-11-14(21)5-2-6-15(11)23-19(26)24-16-8-7-13(20)18(17(16)25)29(27,28)12-4-3-9-22-10-12/h2,5-8,12,22,25H,3-4,9-10H2,1H3,(H2,23,24,26)/t12-/m0/s1

Mechanism of Action: C-X-C Motif Chemokine Receptor 2 (CXCR2) Antagonists; Interleukin 8 Beta Receptor Antagonists

Activity: Management of Chronic Obstructive Pulmonary Disease (COPD); Management of Influenza Virus Infections

Status: Phase Trials

Chemical Class: Small molecules; Flourine containing; Amides, Urea Derivatives; Chlorine containing; Chlorobenzenes; Fluorobenzenes; Piperidine Derivatives; Sulphur containing; Sulfonyl containing

Originator: GlaxoSmithKline
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