By Lisa Seachrist

Washington Editor

Privately held Arena Pharmaceuticals Inc. entered into a collaboration with Fujisawa Pharmaceutical Co. Ltd. to develop a number of orphan G-protein-coupled receptors (GPCRs) as drug-screening targets.

The collaboration is the biggest one to date for San Diego-based Arena, and will focus on neurodegenerative disorders and diseases. The companies aren't disclosing specific details of the deal, but it will include a license fee, milestone payments and royalty payments on sales of any drug products resulting from the collaboration.

"This is our first big collaboration," said Jack Lief, president and CEO for Arena. "We're in discussions with other big pharmaceutical companies, but the first one is always special."

While the exact financial details aren't being disclosed, Lief told BioWorld Today the "typical" Arena deal includes $2 million for each receptor, $20 million in milestones, and subsequent royalty payments.

By modulating the function of GPCRs, which serve as the foundation for the collaboration with Fujisawa, of Osaka, Japan, the pharmaceutical industry has produced an enormous class of drugs including beta-blockers, antihistamines and analgesics. Discovering those drugs has relied upon finding the natural ligands for the individual GPCRs and characterizing the native ligand prior to drug screening. Unfortunately, the natural ligand for most GPCRs is not known, making more conventional drug development methods ineffective. Such receptors are referred to as "orphan" receptors.

"We don't bother with identifying the ligands," Lief said. "It takes a long, long time to find ligands and we estimate there are over 2,000 GPCRs in the human genome. The vast majority of them nobody's been able to screen."

Instead of identifying the ligand, Arena's CART (Constitutively Activated Receptor Technology) uses genetically altered, activated orphan receptors that produce a robust biological signal in the absence of that natural ligand. Using a high-throughput screening assay that measures the most proximal signal, Arena can identify both signal enhancers and signal inhibitors while cutting down on false negative results.

Traditional ligand-dependent screens are limited to identifying compounds serving as antagonists to the action of a ligand on a receptor. These compounds, however, don't affect receptors that are active in the absence of ligand. CART technology allows Arena to discover modulators of this activity as well.

"CART technology allows you to find drugs that are totally invisible when you require ligand binding," Lief said. "Typically, enhancers are more difficult to find."

Under the terms of the Fujisawa agreement, Arena will be responsible for receptor identification, localization and regulation, application of its CART technology to the selected receptors, and validation of screening assays based on the selected receptors. Fujisawa will be responsible for screening its chemical library using selected CART receptor assays, identification of chemical leads, and preclinical and clinical development of ensuing drug candidates. Fujisawa may also screen Arena's in-house chemical library.

Arena is currently screening nine CART-activated orphan GPCRs. These receptors may eventually lead to compounds effective in treating diseases ranging from stroke and dementia to inflammation and diabetes.