Lesogaberan (AZD3355)

Mechanism of action: Gamma-aminobutyric acid receptor B (GABAB) agonist

Preclinical pharmacology

AZD3355 increased intracellular Ca2+ with an EC50 of 8nM in CHO cells transfected with human GABAB1a/2 and displaced radioactive GABA binding from rat brain membranes with an IC50 of 2nM. In a broad enzyme and receptor screen, AZD3355 (10uM) was only found to also interact significantly with GABAA (600 more selective for GABAB) receptors. In the dog, when administered directly into the stomach, AZD3355 reduced transient lower oesophageal sphincter relaxations (TLESRs), producing approximately 50% inhibition at 3mg/kg (compound levels of ~600 x EC50 in plasma).

Safety and tolerability

AZD3355 has been administered to healthy volunteers in single doses of up to 1800mg and in multiple ascending doses of up to 800mg BID for 5 days. In 5 clinical Phase 2 studies, a total of 930 patients have been treated with AZD3355 at oral doses of up to 240mg BID for 4 weeks. Increases, usually mild, in liver enzymes were seen in small numbers (<2%) of subjects on AZD3355 in two of these patient studies; these resolved after treatment was stopped.

Preclinical studies of up to 12 month duration and lifetime bioassays in rat and mouse have been performed. The toxicity profile shows no indication of hepatic effect. AZD3355 has been shown to induce decreased body weight and decreased food consumption. A dose-dependent diuretic effect was also noted in rats.

Clinical pharmacology

In healthy volunteers, AZD3355 dosed at 0.8mg/kg produced a 36% reduction in TLESRs at plasma compound concentrations of ~120 x EC50. In GERD patients, AZD3355 at 65mg BID, compared to placebo as add-on treatment to a proton pump inhibitor (PPI), reduced the number of TLESRs by 25%, increased LES pressure by 28%, and reduced the number of reflux episodes by 47% during 0 to 3 hours post-prandially. In a dose-finding study on GERD symptoms, 4 doses of AZD3355 (60, 120, 180 and 240mg BID) for 4 weeks as add-on to PPI, statistically significant efficacy was demonstrated at the highest dose (response rates of 26% for the treatment group compared to 18% for placebo).

Suitable for and exclusions

Preclinical reprotoxicology data are available and have not identified any specific risks. Women of child-bearing potential using highly effective contraception can be included. Given the potential effects on liver enzymes, dosing regimen (level and duration) as well as inclusion/exclusion criteria should be selected carefully to support a favourable risk-benefit.

Additional Information

Clinical trials for this compound

See all of the clinical trials currently associated with this compound:

Publications for this compound

Find out more about this compound by reading related publications:

Pharmacological evaluation of novel gamma-aminobutyric acid type B

(GABAB) receptor agonists as gastroesophageal reflux inhibitors.

Gene information from the NCBi

This compound works on the following genes: