Selective Prostaglandin D2 Receptor Research Articles

Fevipiprant, a selective prostaglandin D2 receptor 2 antagonist, inhibits human group 2 innate lymphoid cell aggregation and function

Fevipiprant, a selective prostaglandin D2 receptor 2 antagonist, inhibits human group 2 innate lymphoid cell aggregation and function

Sodium [2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-4′-(6-ethoxy-pyridin-3-yl)-6-methoxy-biphenyl-3-yl]-acetate (AM432): A potent, selective prostaglandin D2 receptor antagonist

Compound 21 (AM432) was identified as a potent and selective antagonist of the DP(2) receptor (CRTH2). Modification of a bi-aryl core identified a series of tri-aryl antagonists of which compound 21 proved a viable clinical candidate. AM432 shows excellent potency in a human whole blood eosinophil shape change assay with prolonged incubation, a comparatively long off-rate from the DP(2) receptor, excellent pharmacokinetics in dog and in vivo activity in two mouse models of inflammatory disease after oral dosing.

Hypophosphatemic Effect of Niacin in Patients without Renal Failure

Niacin administration lowers the marked hyperphosphatemia that is characteristic of renal failure. We examined whether niacin administration also reduces serum phosphorus concentrations in patients who have dyslipidemia and are free of advanced renal disease. We performed a post hoc data analysis of serum phosphorus concentrations that had been determined serially (at baseline and weeks 4, 8, 12, 18, and 24) among 1547 patients who had dyslipidemia and were randomly assigned in a 3:2:1 ratio to treatment with extended release niacin (ERN; 1 g/d for 4 weeks and dose advanced to 2 g/d for 20 weeks) combined with the selective prostaglandin D2 receptor subtype 1 inhibitor laropiprant (L; n = 761), ERN alone (n = 518), or placebo (n = 268). Repeated measures analysis revealed that ERN-L treatment resulted in a net mean (95% confidence interval) serum phosphorus change comparing ERN-L with placebo treatment of -0.13 mmol/L (-0.15 to -0.13 mmol/L; -0.41 mg/dl [-0.46 to -0.37 mg/dl]). These results were consistent across the subgroups defined by estimated GFR of <60 or > or =60 ml/min per 1.73 m(2), a serum phosphorus of >1.13 mmol/L (3.5 mg/dl) versus < or =1.13 mmol/L (3.5 mg/dl), the presence of clinical diabetes, or concomitant statin use. We have provided definitive evidence that once-daily ERN-L treatment causes a sustained 0.13-mmol/L (0.4-mg/dl) reduction in serum phosphorus concentrations, approximately 10% from baseline, which is unaffected by estimated GFR ranging from 30 to > or =90 ml/min per 1.73 m(2) (i.e., stages 1 through 3 chronic kidney disease).

What's the deal with niacin development: is laropiprant add-on therapy a winning strategy to beat a straight flush?

Niacin is a B-complex vitamin used as a lipid-altering drug since the 1950s. Niacin improves multiple lipid parameters. Atherosclerotic coronary heart disease outcome studies support niacin's efficacy in reducing coronary heart disease events, either as monotherapy or when used in combination with other lipid-altering drugs. The most commonly reported reason for the lack of its more widespread clinical use is niacin-induced flushing. Laropiprant is a highly selective prostaglandin D2 receptor 1 antagonist that mitigates niacin-induced flushing. This review examines the history and provides a perspective regarding the extended-release niacin/laropiprant development program, which was designed to better allow patients to achieve a more therapeutic niacin dose of 2 g/day, without the need for titration. Ongoing coronary heart disease outcome studies will provide better insight as to the benefits of niacin in general, and the safety and efficacy of extended-release niacin/laropiprant specifically.

A practical synthesis for the core structure of a family of selective prostaglandin D2 receptor antagonists.

A convergent synthesis was developed for the production of the core structure of prostaglandin D(2) receptor antagonists for the treatment of allergic rhinitis. The key steps in this synthesis were a highly diastereoselective alkylation of (+)-nopinone, a chemo- and stereoselective reduction of an oxime to an amine, and a well-controlled reduction of an aminoalkyne to a (Z)-olefin.