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].

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

Summary

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

SMILES:O=S(C1=C(Cl)C=CC(NC(NC2=C(C)C(F)=CC=C2)=O)=C1O)([C@@H]3CNCCC3)=O

InChI Key: NGYNBSHYFOFVLS-LBPRGKRZSA-N

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

Danirixin Synthesis

US20070249672A1: The patent reports synthesis of Danirixin ((S)-1-(4-chloro-2-hydroxy-3-(piperidin-3-ylsulfonyl)phenyl)-3-(3-fluoro-2-methylphenyl)urea) and various intermediates involved in the process.

Intermediate 1:

Danirixin Intermediate-1

Intermediate 2:

Danirixin Intermediate-2

Final Synthesis:

Synthesis of Danirixin

Identifications:

1H NMR (Estimated) for Danirixin

Experimental: ¹H-NMR (MeOD) δ 8.40 (1H, d, ArH), 7.46 (1H, d, ArH), 7.19-7.15 (2H, m, ArH), 6.85 (1H, t, ArH), 4.14 (1H, dt, CH), 3.66 (1H, dd, CH), 3.37 (2H, d, CH₂), 3.04 (1H, dt, CH), 2.19 (3H, S, ArCH₃), 2.14 - 1.69 (4H, m, 2 × CH₂).

Sideeffects: The most commonly reported treatment related adverse event (TEAE) is headache. Nearly 45% of participants in various trials till date have complained of headaches. Importantly, participants did not develop low neutrophil counts or overt neutropenia, as has been reported with other CXCR2 antagonists. Haematology, clinical chemistry and vital sign abnormalities of potential clinical importance were isolated occurrences and were only slightly outside the reference range. There were no clinically significant ECG findings.

Others:

Discovery of Danirixin: In the mid-1990s, a high throughput screening (HTS) campaign at SmithKline Beecham (now GlaxoSmithKline) produced SK and F 83589, the first low molecular weight (LMW) CXCR2 antagonist ever described. SK and F 83589 was shown to compete with [¹²⁵I]-CXCL8 in a binding assay using CHO cell membranes expressing CXCR2 with IC₅₀ of 0.5 uM.

Subsequent optimization focusing primarily on in vitro potency led to the identification of SB-225002, which showed much improved binding affinity ([¹²⁵I]-CXCL8 IC₅₀ = 22 nM). Moreover, SB-225002 displayed excellent antagonistic activity in a Ca²⁺-mobilization (Ca²⁺ IC₅₀ = 30 nM) and CXCL8-mediated neutrophil chemotaxis (IC₅₀ = 20 nM) assay. In addition, SB- 225002 was shown to ameliorate the effects of acute experimental colitis in mice [3].

These 2-hydroxyphenyl ureas have this unique phenolic hydroxyl group which could categorically not be removed or blocked by, for instance, methylation. The potency of this series is attributed to the presence of the phenolic hydroxyl group. Moreover, binding of SK and F 83589 and close analogs as a function of pH indicated that these ureas bind most strongly in their anionic form. As a result, electron-withdrawing substituents in the 3- and 4- positions were preferred. Furthermore, SAR evaluation of the right-hand side (RHS) phenyl ring indicated that substitution of the 20-position increased affinity. Thus, modification of SB-225002 by replacement of the 4-nitro group with a cyano functionality and introduction of a bromine at the 3-position furnished Compound 1 with an [¹²⁵I]-CXCL8 IC₅₀ of 6 nM and equally potent antagonistic activities. Compound 1 had one major drawback as it was rapidly cleared upon systemic administration due to glucuronidation. In order to improve the poor pharmacokinetic (PK) properties, varying substitution at the 3-position was explored. Consequently, introduction of a blocking sulfonamide group, as in compound 2, produced small potency improvements. However, more importantly, sulfonamide demonstrated substantially enhanced PK properties as gauged by the low clearance rate and excellent oral bioavailability in rat [3].

CXCR2 Inhibitors: Small Molecule Antagonists

Danirixin is not a sulfonamide, but it owes it origin in the structure-activity-studies (SAR) of the original sulfonamide bearing ureas as CXCR2 inhibitors.

Neutrophils Management in Chronic Obstructive Pulmonary Disease (COPD): Neutrophils provide innate immune defence against microbes such as bacteria. Neutrophilic airway inflammation is a characteristic feature of chronic obstructive pulmonary disease (COPD) [4].

Neutrophils activated by the inhalation of toxic particles contribute to the pathophysiology of COPD by secreting proteases that cause tissue destruction and by releasing mediators that promote airway inflammation. It could be therapeutically beneficial to reduce neutrophil activity in COPD lungs but one has to be careful about preserving anti-bacterial defence. This is particularly relevant for the subset of COPD patients who have persistent bacterial colonisation and/or acute bacterial exacerbations, often caused by nontypeable Haemophilus influenzae (NTHi) or Streptococcus pneumonia.

The chemokine receptor CXCR2 plays a key role in neutrophil chemotaxis. CXCR2 specific antagonists such as MK-7123 administered for 6 months reduced sputum neutrophil numbers and improved lung function in COPD patients, supporting the concept that reducing neutrophilic airway inflammation is beneficial for COPD patients. However, this orally administered drug excessively reduced blood neutrophil counts in some patients. Furthermore, there were more infections in the optional 12 month extension period in patients treated with MK-7123 compared to placebo. This highlights the balance required with anti-neutrophil therapies in COPD; potential clinical benefit weighed against risk of infection.

Th17 cytokines, including IL-17 and IL-22, fight bacteria by various mechanisms, including the upregulation of anti-microbial proteins and the secretion of neutrophil chemokines, such as CXCL8, by airway epithelial cells. Targeting IL-17A has been beneficial during COPD exacerbations, because of the potential to reduce neutrophilic inflammation while having no detrimental effect on bacterial clearance.

IL-17 may be a useful anti-inflammatory approach in the context of NTHi infection, but not during S. pneumoniae infection where IL-22 comes into play.

The future in COPD management and treatment lies in selective manipulation of these cytokines, thereby bringing an effective neutrophil count where patients cure and safety both will be accounted for.

In the clinic, Danirixin has efficacy at a dose not associated with reduced blood neutrophils. Moreover, competitor compounds such as MK-7123 produced clinical effects, but with reduction in blood neutrophils.

References:

1. Miller, B. E.; et. al. The pharmacokinetics of conventional and bioenhanced tablet formulations of danirixin (GSK1325756) following oral administration in healthy, elderly, human volunteers. Eur J Drug Metab Pharmacokinet 2014, 39(3), 173 - 181. (free article)

2. Miller, B. E.; et. al. The pharmacokinetics and pharmacodynamics of danirixin (GSK1325756) - a selective CXCR2 antagonist - in healthy adult subjects. BMC Pharmacology and Toxicology 2015, 16(18). (free article)

3. Mihara, K.; et. al. Low Molecular Weight CXCR2 Antagonists as Promising Therapeutics. Chap. 12: Chemokine Receptors as Drug Targets. 2011 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim. (FMO only)

4.  Singh, D. Chronic Obstructive Pulmonary Disease, Neutrophils and Bacterial Infection: A Complex Web Involving IL-17 and IL-22 Unravels. EBioMedicine 2015, 2(11), 1580 – 1581. (free article)

5. Busch-Petersen, J. IL-8 Receptor Antagonists. US20070249672A1.

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