GPCRs (G-protein coupled receptors) account for a large percentage of drugs being developed. Researchers at Arena Pharmaceuticals conduct their lead development around the hypothesis of stabilizing the constituitively active form of GPCRs to generate a signal without having to identify the natural ligand prior to discovering a small molecule to that receptor.
This is the basis of their technology CART—constituitively activated receptor technology—which enhances detection and allows simultaneous identity of the receptor inhibitor and activator drug leads.
The company’s initial lead molecule, GPR119, was an inverse agonist. “We used medicinal chemistry,” explained Dominic Behan, Ph.D., cofounder and CSO, “and flipped the activity of the inverse agonist to an agonist. The initial breakthrough was getting a molecule interacting with the receptor, and then designing agonists around that scaffold.”
Another technology uses melanophores, frog skin cells, to measure activity stimulated by GPCRs and by small molecules that target those GPCRs. The pigment in the frog cells will disperse within the cell if it stimulates cyclic AMP, and this is measured by absorption. “This was used in the early discovery of GPR119 and was later evolved into different assays,” said Dr. Behan.
James Leonard, Ph.D., senior director, metabolic disorders, presented the company’s approach to discovering and developing GPR119. Using the firm’s technologies, he said they found that this molecule increased cyclic AMP in insulin-producing cells of the pancreas. “Here we have a novel receptor in the cell type of interest, and it signals in the same way as a receptor (GOP1) with a nontherapeutic benefit. So the strategy was, can we find small molecules and replicate the same biology? In short, that’s what we did.”
Additional research showed GPR119 expression not only in the pancreas, but also in the intestinal endocrine cells (stimulating release of GLP1, GIP, and PYY—all hormones that are known to be beneficial in the regulation of glucose homeostasis, and which are positively regulated by GLP119).
Dr. Leonard said these studies have shown GLP119 has positive effects on oral glucose tolerance and maintains activity when given repeatedly, in addition to showing chronic efficacy in rodent models of type 2 diabetes, with lower HDA1C, improved glucose, and lipid profiles.
There’s little doubt that the global markets for prescription endocrine and metabolic disease drugs will increase. A 2007 report by BCC Research estimated the market would reach $96.4 billion by 2011, up from $72.3 billion in 2006. As research moves forward, there is a great deal of promise for new therapeutics that may not just address the symptoms of metabolic disease but stop disease progression.