Acifran

Acifran: a double-blind, randomized, placebo-controlled efficacy study in type IIa hyperlipoproteinemic patients.[Pubmed:3314798]

Artery. 1987;14(6):338-50.

The antihyperlipoproteinemic agent Acifran (AY-25,712) was administered double-blind to 14 Type IIa hyperlipoproteinemic patients for 12 weeks in dosages of 100 mg t.i.d. or 300 mg t.i.d. An additional seven patients received placebo. Fasting plasma lipid and lipoprotein concentrations were determined at baseline (mean of 3 values), Week 8 (mean of 6- and 8-Week values), and Week 12 (mean of 10- and 12-Week values). At Week 8, patients receiving Acifran 100 mg t.i.d. showed low-density lipoprotein (LDL) cholesterol levels which were 13% lower than pretreatment baseline (p less than 0.01) and 14% lower than patients given placebo (p less than 0.05); high-density lipoprotein (HDL) cholesterol levels were 11% higher compared with either baseline or the placebo group (p less than 0.05); the LDL/HDL ratio was 20% lower than baseline (p less than 0.001) and 21% lower than the placebo group (p less than 0.05); total cholesterol was 8% lower than that of the placebo group (p less than 0.05). There was no apparent relationship between changes in plasma lipid concentrations and Acifran dose or treatment duration except for triglycerides, which at Week 12 were 25% lower than baseline (p less than 0.001) and 35% lower than the placebo group (p less than 0.05) only in the Acifran 300 mg t.i.d. group, in which HDL-cholesterol was concurrently 18% higher compared with placebo (p less than 0.05). In this 12-week study Acifran provided safe and effective treatment for Type IIa hyperlipoproteinemia.

Pharmacokinetics and disposition of the lipid-lowering drug acifran in normal subjects and in patients with renal failure.[Pubmed:2295219]

Clin Pharmacol Ther. 1990 Jan;47(1):50-6.

The pharmacokinetics and metabolic fate of the antihyperlipidemic drug Acifran were assessed after a single oral dose of the 14C-labeled drug to healthy male volunteers. Peak serum Acifran and radioactivity concentrations were attained 1 to 2 hours after dosing, and the drug was eliminated with a half-life of 1.6 hours. Virtually all of the recovered dose was excreted in the urine. All of the serum and urinary radioactivity was caused by unconjugated Acifran. In patients with moderate chronic renal failure, the binding of Acifran to plasma proteins was decreased, and the plasma concentrations of total and unbound drug were greater than those of healthy subjects. Renal failure substantially reduced the plasma and renal clearance of total and particularly of unbound Acifran, moderately reduced its volume of distribution, and increased its elimination half-life from 1.4 to 1.7 hours to 5.7 hours. The results show that Acifran is very well absorbed, is rapidly eliminated, is excreted in the urine, and does not undergo any detectable biotransformation in healthy human subjects.

Analogues of acifran: agonists of the high and low affinity niacin receptors, GPR109a and GPR109b.[Pubmed:17358052]

J Med Chem. 2007 Apr 5;50(7):1445-8.

Recently identified GPCRs, GPR109a and GPR109b, the high and low affinity receptors for niacin, may represent good targets for the development of HDL elevating drugs for the treatment of atherosclerosis. Acifran, an agonist of both receptors, has been tested in human subjects, yet until recently very few analogs had been reported. We describe a series of Acifran analogs prepared using newly developed synthetic pathways and evaluated as agonists for GPR109a and GPR109b, resulting in identification of compounds with improved activity at these receptors.

Triglyceride modulation by acifran analogs: activity towards the niacin high and low affinity G protein-coupled receptors HM74A and HM74.[Pubmed:16389067]

Biochem Biophys Res Commun. 2006 Feb 10;340(2):482-90.

Niacin is known to exert profound beneficial effects on cholesterol levels in humans, although its use is somewhat hampered by the gram quantities necessary to exert effects and the prevalence of compliance-limiting skin flushing side effects that occur. Recently, two G protein-coupled receptors (GPCRs) for niacin were identified and characterized as high (HM74A; GPR109A) and low (HM74; GPR109B) affinity receptors based on the binding affinities of niacin. These receptors also bind Acifran (AY-25,712), which is known to modulate lipid levels like niacin, with similar affinities. Twelve analogs of Acifran were chemically synthesized. One analogue demonstrated a dose-dependent decrease in serum triglycerides in rats within 3h of oral administration. Next, the Acifran analogs were assessed for their activity towards the high and low affinity niacin receptors expressed in CHO-K1 cells. Constructs expressing HM74A or HM74 were stably transfected into CHO-K1 cells and shown to elicit phosphorylation of p42 and p44 mitogen-activated protein kinase (ERK1/ERK2) phosphorylation upon addition of niacin or Acifran. The presence of functionally coupled GPCRs was further confirmed using Pertussis toxin, which completely inhibited the ability of either niacin or Acifran to elicit phospho-ERK1/ERK2. The EC(50) of p-ERK1/ERK2 for niacin for the high and low affinity receptors was 47nM and indeterminate (i.e., >100microM), respectively, while the EC(50) for Acifran was 160 and 316nM, respectively. Two chemical analogs of Acifran demonstrated robust phosphorylation of ERK1/ERK2. Collectively, these data suggest that the synthesis of Acifran analogs may be a suitable path for developing improved HM74A agonists.