First-in-class potential

Anti-Asthmatic

original drug candidate GUR-501

Challenge

There are only two main groups of drugs involved in regulation of bronchial tone. The first group includes β2-agonists (alupent, ventolin, salbutamol, berotec, etc.) and the second group includes mcholinoblockers (atropine and its analogs). However, application of β2-agonists is often accompanied by serious side effects and chronic application or overdose usually result in the loss of clinical efficacy. M-cholinoblockers cause multiple side effects and aren't applied independently but typically with β2-agonists.

Solution

There is a third, not used so far, type of targets for regulation of bronchial tone. This is EP4 receptor for prostaglandin Е2 (PGE2). Relaxing effect of PGE2 on bronchial smooth muscle is as strong as that of β2-agonists, but at the same time the side effects can be significantly reduced, since it is a natural endogenous bioregulator. GUR-501 as modified PGE2 doesn't provoke a cough reflex unlike to the initial prostaglandin PGE2. GUR-501 has up to 50 times more activity on bronhi muscles. In addition, there is no side effect of capillary dilation leading to edema of the bronchi, which can be observed when using β2- agonists. Second potential biological target for GUR-501 (after NO releasing) may be soluble guanylate cyclase. Thus, GUR-501 may be the only effective drug for patients with long-term asthma who have developed tolerance to existing bronchodilators.

General information

Therapeutic Area: Asthma and bronchospasm treatment (ATC R03, bronchodilator).
Innovative status: original individual molecule, first in class potential.
Planned formulation: liquid formulation for nebulaizer powder for dry inhaler.
Type of molecule: small molecule, natural prostaglandin + NO donor part
Development stage: Completed preclinical

Drug design

Pharmacologic effect is provided by the combined synchronized multitarget action of a hybrid compound consisting of natural prostaglandin pharmacophore linked to NO-donor component.

 

 

Pharmacology and Features

  • Very high bronchodilatory activity, up to 50 times higher than activity of PGE2 (in vitro, ex vivo)
  • No changes in frequency of heart beats
  • No tachyphylaxis (supposed)
  • Good compatibility to other types of broncholytics.

Action on smooth muscles

Ratio between the specific activity (relaxation of tracheal smooth muscles) and undesired activity (constriction of smooth muscles of stomach or uterus) is increased by 2 orders of magnitude as compared to natural PGE2

Mechanism of action and biotargets

1. Bronchial prostanoid EP4 and EP2 receptors.
According new data natural prostaglandins can relax human bronchial smooth muscles via action on specific EP4-receptors ((Buckley J et al., 2011, Benyahia C. et al.. 2012)). However, inhalations of natural PGE2 but not GUR-501 leads to undesired effects (cough, etc.) due to action on prostanoid EP3 receptor.

2. Soluble guanylyl cyclase for Nitric oxide.
Prostaglandin part of the hybrid molecule GUR-501 provides targeted delivery of another well known bronchodilator – NO – to the site of action. This guanylate cyclase enzyme binds the released NO and transfers a molecular signal in form of cyclic guanosine monophosphate.

3. Receptors for PGE2-glycerol ester. It requires clarification of MOA

Toxicity

  • LD50 3800 mg/kg (mice, iv) – low toxic
  • Daily intraperitoneal administration to mice (doses 50 and 500 mg/kg) for 14 days does not lead to toxic effects
  • Therapeutic index (ratio of acute toxicity (LD50) to bronchodilating activity (EC50)) > 10 000

Prospective competitive advantages

  • New target(s) for regulation of bronchial tone.
  • Fast, pronounced therapeutic effect.
  • Effective even after prolonged use.
  • Virtually no or imperceptible side effects.
  • Great potential for patenting complex preparations

Other properties

  • GUR-501 has general favorable effects on cardiovascular system (vasoactive)
  • Stable for at least 1 year at -4 °C
  • Soluble in organic solvents, poorly soluble in water

Technology

  • Synthesis technology from natural precursor is well reproducible.
  • Global demand in the substance can be met by laboratory capacity due to very small inhalation dose (7-10 mcg).
  • Analytical procedures (HPLC, IR, NMR, MS) are well developed and validated.
  • Developed FDF for nebulizer.

Very promising potential

GUR-501 is a new generation drug with novel target-specific activity and mechanism of action. It is compatible with the existing bronchodilators, which makes possible various original compositions of active ingredients with very promising pharmacological effects.