PRELIMINARY ASSESSEMENT OF GASTRODUODENAL AND RENAL SAFETY PROFILE OF A NOVEL SELECTIVE MICROSOMAL PROSTAGLANDIN E SYNTHASE 1 INHIBITOR

Carla Landolfi, Giuseppe Santo, Isabella Coletta, Lorenzo Polenzani, Lucia Durando, and Giovanni Battista Ciottoli. Angelini Research Center – ACRAF SpA, S.Palomba-Pomezia, Roma

Introduction Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme that couples cyclooxygenase (COX) isoforms to produce prostaglandin E2 (PGE2). PGE2 plays a key role in multiple physiological processes including reproduction, bone metabolism and kidney function, as well as in a number of pathological conditions such as inflammation, pain, fever, and cancer. Selective inhibition of mPGES-1 could overcome some of the adverse effects of unselective COX inhibitors (NSAIDs), e.g. gastrointestinal or renal side-effects and COX-2 inhibitors (Coxibs), e.g. increased cardiovascular risks, suppressing selectively inflammatory PGE2 production without affecting the other classes of prostanoids release and their physiological functions. AF3485 is a novel mPGES-1 selective inhibitor synthesized in Angelini Research Center. In previous studies, AF3485 selectively inhibited mPGES-1 in several human in vitro systems and showed antipyretic, analgesic and anti-inflammatory effects in mice and rats in the range of 3-10 mg/kg po. Aim The purpose of this study was to investigate the preliminary gastrointestinal and renal safety profile in rats of AF3485, in comparison with anti-inflammatory compounds such as indomethacin, and diclofenac, non-selective COX inhibitors, and celecoxib, a selective COX-2 inhibitor. Methods In order to investigate potential side effects on the gastrointestinal mucosa of a single oral administration of AF3485 270 mg/kg/10ml, CD male fasted rats (101-125 g, n=5/group) were used in two different experimental models for gastric and intestinal ulcerogenic assessment. Ulcerogenic activity, measured as severity index, was compared to that of indomethacin, diclofenac and celecoxib, used as reference. The interference of a single oral administration of AF3485 270 mg/kg/25ml with fluid and electrolyte homeostasis was evaluated in comparison with celecoxib in saline-loaded CD male rats (177-229 g, n=9/group). After treatment rats were individually housed in metabolic cages in fasted condition. Urinary salt excretion was assessed in urine collected for 6 hours after dosing using an electrolyte analyzer. Results Our results showed that the mPGES-1 selective inhibitor AF3485 does not cause NSAID-like gastrointestinal toxic effects such as mucosal erosions or renal side effects like interference with fluid and electrolyte homeostasis in the rat. In the same experimental conditions, reference drugs resulted in gastrointestinal and/or renal side effects as expected.