Herein, we describe a general method for the synthesis of unsymmetric diarylmethanes from (hetero)aryl methyl halides and Sb-aryl stibines. This protocol shows a broad substrate scope and a good functional group tolerance. Drug molecules, including beclobrate 3al and bifemelane 3as, and drug derivatives, including celecoxib 3p, ibuprofen 3ao, and probenecid 3ap, were efficiently synthesized on a gram scale. The possible mechanism is proposed on the basis of the results of control experiments.

01 Jan 1993·ChiralityQ4 · CHEMISTRY

In vitro and in vivo irreversible plasma protein binding of beclobric acid enantiomers

Q4 · CHEMISTRY

Article

Author: Leslie Z. Benet ; Ernst Mutschler ; Sascha Mayer ; Hildegard Spahn‐Langguth

AbstractAcyl glucuronides are known to be labile conjugates, which undergo hydrolysis and bind irreversibly to proteins. The lipid‐regulating agent (±)‐beclobrate is immediately converted to the free acid after oral administration. Further metabolism leads to formation of the corresponding diastereomeric acyl glucuronides. Beclobric acid glucuronides were quantified by indirect measurement with an HPLC method based on chiral fluorescent derivatization of the carboxylic acid and subsequent normal‐phase chromatography. The renal clearance of unchanged drug is low, with almost all drug excreted into urine as glucuronic acid conjugates. Beclobric acid glucuronide is also detectable in plasma. In vitro degradation studies with beclobric acid glucuronide (at a concentration of 5 μM in 150 mM phosphate buffer pH 7.4) exhibited a minor tendency for acyl migration and hydrolysis, i.e., a higher stability than has been observed for the acyl glucuronides of most other drugs. The in vitro degradation half‐lives of the two beclobric acid β‐1‐O‐acyl glucuronides were 22.7 and 25.7 h. After incubation with pooled plasma and human serum albumin in buffer pH 7.4 irreversible binding was measured in vitro. No significant difference between the two enantiomers was detected with respect to the magnitude of in vitro irreversible binding. In 3 healthy male volunteers the extent of irreversible binding of both beclobric acid enantiomers to plasma proteins was investigated after single and multiple oral doses of racemic beclobrate (100 mg once daily). Irreversible binding of both enantiomers was observed in all volunteers. The adduct densities for (−)‐ and (+)‐beclobric acid after single 100 mg beclobrate doses were 0.147 × 10−4 and 0.177 × 10−4 mol/mol protein. Multipie dosing increased irreversible binding 3‐ to 4‐fold. © 1993 Wiley‐Liss, Inc.

01 Jan 1993·Arzneimittel-Forschung

Pharmacokinetics of beclobric acid enantiomers and their conjugates after single and multiple oral dosage of racemic beclobrate.

Article

Author: Mutschler, E ; Mayer, S ; Gikalov, I ; Spahn-Langguth, H

The chiral lipid regulating agent beclobrate (CAS 55937-99-0), which was marketed as racemate, is - like clofibrate - rapidly hydrolyzed to beclobric acid immediately after absorption. Pharmacokinetic data were only available for the total concentration, but not for the two enantiomers. Therefore, the pharmacokinetics of (-)- and (+)-beclobric acid were studied in 8 healthy male volunteers after a single 100 mg dose of rac-beclobrate and under steady state conditions, i.e. after repetitive dosage of 100 mg beclobrate once daily for 8 days. After oral administration unchanged beclobrate was not detected in plasma. Distinct differences were found in the pharmacokinetic parameters of the two beclobric acid enantiomers. The maximum plasma concentrations and the AUC values of the (+)-enantiomer exceeded those of the (-)-enantiomer nearly 2 fold. Beclobric acid, the active metabolite, is converted to an acyl glucuronide. The diastereomeric glucuronides were detected in the plasma of all volunteers, but the differences in the pharmacokinetics were not as evident as for beclobric acid enantiomers. A comparison of the measured steady-state beclobric acid enantiomer concentration and those simulated on the basis of the parameters (open two-compartment model) obtained for a single beclobrate dose showed that the accumulation factor is slightly but nevertheless significantly higher than predicted.

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Indication	Highest Phase	Country/Location	Organization	Date
Hyperlipidemias	Phase 2	DE	University of Freiburg	01 Jan 1991

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