NC/OFQ analogs as ORL1 agonists to promote gut motility


Principal Investigator: Mark A Findeis
Abstract: The purpose of the research proposed by Satori Pharmaceuticals Incorporated is to develop drug candidates for the treatment of gastrointestinal (Gl) disease in which bowel motility is compromised. The primary clinical target for these drugs is postoperative ileus (POI) with further utility for the treatment of other Gl motilityrelated disorders, particularly severe constipation. POI is a condition characterized by a lack of bowel motility, abdominal pain, and nausea. Clinically, POI has serious impact on patient morbidity, causing patient discomfort and prolongation of hospitalization by 3 to 10 days. Delay in resuming normal diet is associated with increased catabolism, risk of malnourishment, hypoalbuminemia, and poor healing. POI may also lead to clinically dangerous conditions, bowel perforation may lead to peritonitis, septacaemia and mortality. POI is the most common condition prolonging hospital stays in the United States and Europe. In the US alone, this additional hospitalization and associated care is estimated to account for nearly $1 billion in increased healthcare costs. Targeted therapies that reduce POI and decrease the length of stay will have a significant impact on patient wellbeing, patient care, and the cost to society for this condition. The strategy proposed is to design and synthesize novel agonists of the orphanin/nociceptin receptor (ORL1, OP4) that are analogs of the endogenous ligand of ORL1, nociceptin (NC), also known as orphanin FQ (NC/OFQ). ORL1 is a G protein coupled receptor, with high homology to other known opiod receptors, that activates calcium ion channels. Using existing structure-activity relationship (SAR) data available on analogs and derivatives of NC, specific changes will be made in NC structure to improve receptor affinity while preserving full agonist behavior. Phase I work will be to synthesize a limited number of reported NC analogs and related compounds to confirm their activity as high-affinity agonists of hORL1. Approximately 24 peptides and peptide mimetics will be synthesized, purified and physicochemically characterized. These compounds will then be assayed for receptor affinity, receptor stimulation, and in vitro biostability (particularly improved peptidase resistance). Using data from these experiments, the Phase II research will focus on lead optimization of novel proprietary hORL1 agonists suitable for evaluation as candidates for clinical development. Compounds will be evaluated using both in vitro and in vivo assays to select a candidate for preclinical evaluation for use as a prokinetic agent to treat postoperative ileus.
Funding Period: 2005-09-30 - 2006-12-31
more information: NIH RePORT