Trial Status and Future Prospects

To date, three pharmaceutical companies have entered clinical trials with PHD inhibitors for the treatment of anemia with the most advanced being FG-2216. In clinical studies, compound 2 (likely FG-2216) showed a dose- and time-dependent elevation of plasma erythropoietin after oral administration [66]. Healthy volunteers were orally administered various doses of compound 2 and serum erythropoietin (EPO) concentrations were measured at various times. Compound 2 increased serum EPO levels in a dose-dependent manner and, following administration of the 20 mg/kg dose, a 5-fold increase of EPO levels was observed after 12 h. In the same patent application, the effect of 2 on anemic predialysis patients with no previous rh-EPO exposure was also disclosed. Patients were treated with 2 three times/week for 4 weeks (no dose reported) and the hemoglobin levels were assessed on day 42. The patients who received treatment showed a mean increase in hemoglobin of 1.9 g/dL from baseline values, whereas subjects who received placebo showed a mean decrease of 0.35 g/dL from baseline levels. These data suggest for the first time that an oral PHD inhibitor could be effective for the treatment of anemia. 

A study of GSK1278863A (structure undisclosed) in healthy adult subjects for the safety, tolerability, pharmacokinetics, and pharmacodynamics of repeat oral doses up to 300 mg for 14 days has also been completed [69]. Finally, AKB-6548 (structure undisclosed) has completed Phase la clinical trials in 48 healthy volunteers for the potential treatment of anemia. Preliminary results claim that doses that significantly increase plasma EPO without raising VEGF levels were identified and that further clinical trials are planned [70]. 

While the role of PHD inhibitors in the treatment of anemia is now validated, therapeutic validation is less certain in other HIF-associated pathologies such as wound healing, ulcerative colitis, therapeutic angiogenesis, and treatment of acute ischemic events such as myocardial ischemia and stroke. All of these indications are supported by a compelling array of in vitro and in vivo preclinical studies but their utility in the clinical setting remains to be evaluated and represents exciting possibilities for the future of small-molecule inhibitors of PHD enzymes. 

Editors Joel C. Barrish and David Weinstein Bristol-Myers Squibb R D Princeton New Jersey 

The G protein-coupled opioid receptors, i (MOR), 6 (DOR), and i (KOR), are expressed in both the central nervous system (CNS) and a variety of peripheral tissues [1]. Opioid analgesics such as morphine, fentanyl, and oxycodone induce analgesia, miosis, and respiratory depression via activation of MOR in the CNS. However, these drugs also have significant inhibitory effects on GI function, including motility, secretion, absorption, and blood flow via MOR expressed in the enteric nervous system (ENS) in the gut [2]. Indeed, opioid-induced constipation (OIC) is an 

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