Drugs in Clinical Pipeline: TRV734 | Treatment of Acute Severe Pain | G Protein-Biased μ-Opioid receptor

TRV734 is novel, potent, and selective G protein-biased μ-opioid receptor ligand. TRV734 robustly engage G protein coupling with efficacy and potency comparable to morphine, but display dramatically reduced β-arrestin coupling. In rodents, TRV734 is potently analgesic, but display reduced gastrointestinal dysfunction (GI) compared to morphine. The improved therapeutic index TRV734 could allow safer, more effective pain management by removing key barriers to effective opioid therapy.

Data from Trevena suggest that oral TRV734 may deliver powerful analgesia with better tolerability than currently used oral opioids for acute and chronic pain.

Drugs in Clinical Pipeline: Oliceridine | Treatment of Acute Severe Pain | G Protein-Biased μ-Opioid receptor

Oliceridine (also known as TRV130) is a G-protein-biased ligand at the μ-opioid receptor. In preclinical studies, it was potently analgesic while causing less respiratory depression and gastrointestinal dysfunction than morphine, suggesting unique benefits in acute pain management. This unique “G protein-biased” μ-opioid ligand is a potent analgesic in rodents, with 3-10 times the potency of morphine, but with reduced gastrointestinal (GI) dysfunction and respiratory depression compared to equianalgesic doses of morphine.

The margin between Oliceridine analgesia and side effects (therapeutic index) in rodents suggests that Oliceridine may be a safer, tolerable analgesic than current parenterally administered opioids such as morphine, fentanyl, and hydromorphone. It is currently in Phase-III trials.

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: Resunab

Resunab [1',1'-dimethylheptyl- Δ⁸-tetrahydrocannabinol-11-oic acid] is developed to achieve the goal of providing a synthetic Cannabis-derived drug that would show analgesic efficacy and have a low potential for abuse. This idea is proven through various experiments where there is no evidence that Resunab produces psychotropic actions when given at therapeutic doses. In a variety of animal assays, Resunab shows efficacy in models for pain and inflammation. Furthermore, in the rat adjuvant arthritis model, Resunab displayed a remarkable action in preventing the destruction of inflamed joints.

Resunab as a novel synthetic oral drug has the potential to treat chronic inflammation and fibrosis. Pre-clinical and Phase 1 studies have shown Resunab to have a favourable safety, tolerability and pharmacokinetic profile. Resunab is designed to trigger the resolution of chronic inflammation by binding to and activating the CB2 receptor on immune cells (in effect, turning inflammation "off"). Resunab holds the potential to be a safe and potent anti-inflammatory drug with a unique mechanism of action to treat a range of chronic inflammatory diseases.

In June 2015, Corbus Pharma announced that the U.S. Food and Drug Administration (US-FDA) has granted Corbus' lead drug candidate Resunab, Orphan Drug Designation for the treatment of systemic sclerosis. Systemic sclerosis is a chronic, serious, life-threatening inflammatory disease causing fibrosis of skin and internal organs, affecting predominately women in mid-life. Systemic sclerosis is associated with severe morbidity and high mortality. There are currently no FDA-approved drug therapies for systemic sclerosis.

The FDA has already cleared the Corbus' investigational new drug application (IND) for systemic sclerosis and the company is preparing to commence Phase 2 studies.

Common Name: Resunab

Synonyms:  Ajulemic acid; AJA; CT-3; IP-751; AB-III-56; HU-239; CPL 7075

IUPAC Name: (6aR,10aR)-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-Dibenzo(b,d)pyran-9-carboxylic acid

CAS Number: 137945-48-3

SMILES: CC(C)(CCCCCC)c2cc1OC(C)(C)[C@@H]3/C=C\C(C[C@H]3c1c(O)c2)C(O)=O

Mechanism of Action: 

Indication: Anti-inflammatory Drugs; Analgesic Drugs; Treatment of Systemic Sclerosis

Development Stage: Phase II

Company: Corbus Pharma

The studies into mechanism of Resunab have produced some contradictory questions.  On the one hand, modest binding to the known cannabinoid receptors, CB1 and CB2 has been reported, and effects by receptor specific antagonists as well as stereospecificity has been observed suggesting a possible role for these receptors in the actions of Resunab. On the other hand, the fact that Resunab does not produce psychoactivity, a process that is believed to require the activation of CB1, appears to be a contradiction. A possible explanation is that Resunab, in addition to activating the receptor, selectively antagonizes a downstream event that is required for psychotropic activity but is not needed for anti-inflammatory actions [1].

References:
1. Burstein, S. Ajulemic acid (IP-751): synthesis, proof of principle, toxicity studies, and clinical trials. AAPS J 2005, 7(1), E143-8.