Friday, September 15, 2017

Drugs in Clinical Pipeline: GRC 27864 | Microsomal Prostaglandin E Synthase-1 (mPGES-1) Inhibitor | Treatment for Chronic Inflammatory Diseases

GRC 27864 is a potent, selective, orally bioavailable inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1). Prostaglandins (PGs) are an important class of lipids related both to physiological and pathological conditions. Among them, prostaglandin E2 (PGE2) is a key mediator of inflammation, pain and fever, but it is also important for the protection of the gastrointestinal mucosa, nutriuresis, blood pressure regulation, and ovulation.

Microsomal prostaglandin E2 synthase-1 (mPGES-1) catalyzes the terminal step of prostaglandin E2 (PGE2) generation. mPGES-1 is strongly upregulated in inflamed tissues and overexpressed in tumors. mPGES-1 inhibitors may be safer anti-inflammatory agents overcoming the side effects of NSAIDs and COX-2 inhibitors.

Thursday, September 14, 2017

Drugs in Clinical Pipeline: BI 409306 | PDE9A Inhibitor | Phosphodiesterase 9A Inhibitors | Treatment for Alzheimer's Disease

Phosphodiesterases (PDEs) in the brain have shown to play an important role in synaptic plasticity and cognitive function. Among those PDEs is PDE9A, which specifically regulates the second messenger cGMP in neurons related to NMDA receptor signaling and is expressed in cognition relevant regions of the brain. Thus, PDE9A inhibitors are hypothesized to improve cognitive function via increasing NMDA receptor related cGMP signalling pathway to strengthen synaptic plasticity.

BI 409306 is a potent PDE9A inhibitor, which strengthens synaptic plasticity as demonstrated by increased hippocampal long-term potentiation (LTP). Systemic application of BI 409306 to rats increased cGMP levels in the CSF and brain indicating functional target engagement. Moreover, BI 409306 shows low nanomolar potency against PDE9A.

Wednesday, September 13, 2017

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.