- ARI-2243 is an highly potent DPP-4 inhibitor, possessing Ki of 27 pM

- ARI-2243 induces superior reduction in plasma glucose

- ARI-2243 produced compelling reduction in HbA1c in refractory diabetic animal model

- ARI-2243 is highly selective to DPP-4 through its proprietary soft drug inactivation

- ARI-2243 is long acting and orally active

Arisaph Pharmaceuticals, Inc., a privately held drug discovery biopharmaceutical company, announced the results of its potent, smart DPP-4 inhibitor, ARI-2243, presented at the 67th session of the American Diabetes Association meeting in Chicago, Illinois. The results showed that ARI-2243 is an extremely long acting, potent inhibitor of DPP-4 and produced superior reductions in plasma glucose compared with sitagliptin in oral glucose tolerance test (OGTT) in mice. Additionally, ARI-2243 produced significant reduction in hemoglobin A1c levels (HbA1c) following 9 weeks of daily oral dosing in an highly refractory diabetic animal model compared with no significant change with vildagliptin. The long-acting and potent attributes of ARI-2243 are expected to confer a differentiated efficacy profile in diabetic patients. Arisaph is currently completing IND enabling studies and expects to initiate first-in-man testing in 2008.

Arisaph designed ARI-2243 as a once a day, orally active, smart DPP-4 inhibitor that is highly potent and functionally selective. In vitro kinetic studies show that ARI-2243 has an affinity (Ki) of 27 picomolar, binding tightly to DPP-4 and dissociating very slowly from the enzyme. Such binding kinetics confer potency and long activity. Specifically, during OGTT in normal mice, ARI-2243 produced far greater lowering of plasma glucose compared with sitagliptin. Specifically, the ED50 with ARI-2243 was 0.006 mg/kg compared with sitagliptin, which had an ED50 of 1.5 mg/kg. Moreover, at 18 hours post dose, ARI-2243 lowered plasma AUC 25%, demonstrating long duration of action of the smart inhibitor.

In ZDF rats, an animal model that develops overt diabetes, ARI-2243 produced a significant reduction in HbA1c of 2.5% and 2.2% versus placebo and vildagliptin, respectively following eight weeks of therapy. Additionally, animals treated with 3.0 mg/kg of ARI-2243 showed less diabetes progression than animals treated with placebo or 3.0 mg/kg of vildagliptin. Such superior efficacy data in an highly refractory diabetes animal model suggest that ARI- 2243 will produce a differentiated efficacy profile in human type II diabetes.

In addition to the compelling efficacy, ARI-2243 is functionally selective through a smart, soft drug inactivation process. Specifically, ARI-2243 binds rapidly and tightly to DPP-4 and once bound, the complex dissociates very slowly, thereby preventing the degradation of GLP-1 at the site of action. Unbound ARI-2243 then undergoes a unique soft drug inactivation as it passes through the gut and into the systemic circulation, which limits the exposure of the active species to unwanted targets, such as DPP 8 and 9. The conversion product, ARI 2498 is a millimolar inhibitor of the DPP family, in particular, DPP 8 and 9. Such soft drug inactivation confers functional selectivity and contributes to a favorable therapeutic window in animals.

"In ARI-2243, we have designed a smart, long acting DPP-4 inhibitor that is extremely potent and functionally selective," commented Christopher P. Kiritsy, President and Chief Executive Officer of Arisaph Pharmaceuticals. "The preclinical efficacy data presented at the ADA highlight the compelling efficacy of ARI-2243 at low doses. With such promising data, we expect to achieve superior HbA1c lowering in humans using significantly lower doses of ARI-2243, thereby supporting our goal of developing best-in-class medicines for validated targets."

Source: Arisaph Pharmaceuticals, Inc.

For more information: http://www.arisaph.com/