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).

Drugs in Clinical Pipeline: GRC-17536

GRC-17536 is an orally available, potent and selective inhibitor of Transient Receptor Potential Ankyrin 1 (TRPA1) with IC₅₀ value less than 10 nM. Moreover, it shows more than 1000 fold selectivity over other TRPs, a large panel of GPCRs, enzymes and other ion channels. It has proven highly efficacious in treating inflammatory and neuropathic pain in animal models compared to other commercial drugs. It reversed hyperalgesia in in vivo models of Freund's complete adjuvant. In addition, when tested in an in vivo model of asthma, it showed promising effect on airway inflammation, bronchoconstriction and cough. The compound has showed good safety in the safety pharmacology and toxicology studies performed till date. GRC-17536 blocked allyl isothiocyanate (AITC), Formalin, 4-HNE, H₂O₂ crotonaldehyde and15-dPGJ₂ activated human TRPA1 receptor with IC₅₀ in narrow range of 1 to 6 nM [1].

At present, GRC-17536 is the only TRP ligand announced as candidate to clinical investigation for the treatment of respiratory disorders as well as an analgesic drug. GRC-17536 will be formulated to be administered via the inhaled route to be used in the respiratory indications. Good efficacy has been observed for GRC-17536 when administered via inhaled route in preclinical pharmacology studies. In guinea pig asthma model of ovalbumin-induced pulmonary eosinophilia, GRC-17536 (100 mg/kg, i.p.) completely attenuated eosinophilia in bronchoalveolar lavage fluid comparable with the PDE-4 inhibitor Roflumilast (1 mg/kg, p.o.). At the same dose, it also inhibited AITC-induced cough response by 60%. These effects of GRC 17536 can be attributed to TRPA1 receptor blockade. GRC 17536 holds promise for potential treatment of respiratory disorders like asthma and  chronic obstructive pulmonary disease (COPD).

The activity of GRC-17536 is as follows:

IC₅₀ (TRPA1 biochemical assay) = less than 10 nM

Common Name: GRC-17536

Synonyms: GRC-17536; GRC17536; GRC 17536

IUPAC Name:

CAS Number: 

Mechanism of Action: TRPA1 Inhibitor; Transient Receptor Potential Ankyrin 1 Inhibitor

Indication: Treatment of Pain; Analgesic Drugs; Anti-inflammatory Drugs; Treatment of Respiratory Disorders; Treatment of COPD; Antitussives

Development Stage: Phase II

Company: Glenmark Pharmaceuticals


Asthma and  chronic obstructive pulmonary disease (COPD) are complex, multi-component respiratory diseases involving persistent airway inflammation. Current anti-inflammatory therapies, such as corticosteroids and others, do not fulfill the critertia for a successful treatment. Transient receptor potential ankyrin 1 channel (TRPA1) is emerging as an attractive target for therapeutic intervention of respiratory diseases. TRPA1 receptor is expressed on airway sensory neurons. It is activated by various components of inflammatory soup and multiple pro-tussive stimuli including cigarette smoke. It is therefore implicated in airway inflammation and sensory responses. Thus, TRPA1 receptor blockade provides a novel mechanism for treatment of inflammatory airways disorders such as asthma and COPD.

Whats the structure for GRC-17536?

Till date, Glenmark Pharma has not disclosed the structure for GRC-17536. As a matter of fact, Glenmark has not disclosed anything about their molecules in clinical trials. Net searches are proof to that. One can find few news items about their work but nothing substantial about their molecules.

In a publication from year 2015 [2], Glenmark has claimed the molecules with IUPAC name N-{4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-di-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide (structure below) a TRPA1 inhibitor as active ingredient.

The hTRPA1 IC₅₀ is below 50 nM for this molecule, but it has poor solubility (less than 0.2 ug/mL).  This issue was addressed by a patent filed by Glenmark, wherein a solubility-enhancing methylene phosphate group was incorporated on the thiazole ring. This change had a detrimental effect on potency relative to their parent compound (IC₅₀ = 100-500 nM) however, both the solubility (greater than 1200 ug/mL) and rat Drug Metabolism and Pharmacokinetics (DMPK) profile of the phosphates was greatly improved. Subsitutuion with methylene phosphate group showed many fold rise in C_max (from less than 250 to greater than 4000 ng/mL) and AUC_0-24 values (from less than 4000 to greater than 50000 ng h/mL).

References:
1. Joshi, N.; et. al. GRC 17536, a novel, selective TRPA1 antagonist for potential treatment of respiratory disorders. European Respiratory Society, Annual Congress; 18-22 September 2010; Barcelona, Spain. (here)
2. Gullapalli, S.; et. al. Pharmaceutical Composition Comprising A Trpa1 Antagonist And An Analgesic Agent. US20150105406A1 

Drugs in Clinical Pipeline: GSK-2269557 | Treatment of COPD | Treatment of Asthma | Treatment of Autoimmune Diseases I PIK3d Inhibitor

GSK-2269557 [2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole] is a potent, selective nanomolar inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA phosphoinositide-3 kinases (PI3K). GSK-2269557 is more selective for PI3Kδ relative to other PI3K class I enzymes (pK_i: PI3Kδ = 9.9) with greater than 1000-fold selectivity over PI3Kα, PI3Kγ and PI3Kβ. It has a pIC₅₀ value greater than 7, with at least ten-fold selectivity for PI3Kδ over PI3Kα, PI3Kγ and PI3Kβ [1, 2].

GSK-2269557: 2D and 3D Structure

GSK-2269557 and GSK-2292767 are designed especially for the treatment of respiratory indications via inhalation. Both the drugs meet the criteria necessary for compounds to be delivered as aerosolized dry powder formulations. The advantages of delivering such inhibitors by this route are that it can minimize the risk of systemic, mechanism-related side effects and it also facilitates exploring combinations of the PI3Kδ inhibitors with other anti-asthma agents such as the corticosteroids [3]. 

GSK-2269557 is currently in Phase 2 clinical trials for chronic obstructive pulmonary disease (COPD) and asthma.

The activity of GSK-2269557 is as follows:

pIC₅₀ (PI3Kδ enzyme assay) = greater than 7

pK_i (PI3Kδ enzyme assay) = 9.9

Common Name: GSK-2269557

Synonyms: GSK-2269557; GSK2269557; GSK 2269557

IUPAC Name: 2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole

SMILES: 

CAS Number: 1254036-71-9; 1254036-77-5 (hydrochloride)

Mechanism of Action: Kinase Inhibitor; PI3K Inhibitor; PI3K delta Inhibitor

Indication: Treatment of COPD; Treatment of Asthma; Treatment of Autoimmune Diseases

Development Stage: Phase II

Company: GlaxoSmithKline

1H NMR (Estimated) for GSK-2269557

References:
1. Hamblin, J. N.; et. al. Oxazole substituted indazoles as pi3-kinase inhibitors. WO2010125082A1
2. Down, K.; et. al. Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase d for the Treatment of Respiratory Disease. J Med Chem 2015, 58(18), 7381-7399.
3. Norman, P. Evaluation of WO2012032067 and WO2012055846: two selective PI3Kd inhibitors, which is GSK-2269557? Expert Opin Ther Pat 2012, 22(8), 965-970.