Degradation pathways study of the natriuretic and β-adrenoceptor antagonist tienoxolol using liquid chromatography–electrospray ionization multistage mass spectrometry

Q3 · MEDICINE

Article

Author: Céolin, René ; Gana, Ines ; Safta, Fathi ; Guechot, Christophe ; Henriet, Théo ; Bernard, Mélisande ; Yagoubi, Najet ; Dugay, Annabelle ; Teulon, Jean-Marie ; Do, Bernard ; Rietveld, Ivo B

Tienoxolol is a pharmacologically active molecule designed with the functional groups ketothiophene, alkyl benzoate and arylpropanolamine so as to combine a diuretic and a β-adrenoreceptor antagonist into a single molecule. Its degradation products generated in several stress media have been determined by high-pressure liquid chromatography (HPLC) coupled to a hybrid mass spectrometer with a triple quadrupole-linear trap. A Polaris(®) column with a C18-A stationary phase and a linear gradient mobile phase composed of a mixture of trifluoroacetic acid 1% (v/v) and acetonitrile allowed for optimal separation. Structural elucidation of the degradation products has been based on MS/MS techniques, by comparing their fragmentation patterns to the precursor's data. Up to seven degradation products of the active ingredient, resulting from hydrolysis, oxidation, dehydration and transamidation have been identified, covering a range of possible degradation pathways for derivatives with such functional groups. Kinetics have been studied to assess the molecule's shelf life and to identify the most important degradation factor.

01 Jan 2012·International Journal of PharmaceuticsQ2 · MEDICINE

Crystal structure and solid-state studies of aged samples of tienoxolol, an API designed against hypertension

Q2 · MEDICINE

Article

Author: Maria Barrio ; Christophe Guéchot ; Ivo B. Rietveld ; Béatrice Nicolaï ; Josep-Lluís Tamarit ; Jean-Marie Teulon ; Bernard Do ; Nathalie Mahé ; René Céolin

Aging of drug molecules is generally studied following regulatory procedures, i.e. under forced conditions and for relatively limited storage time; therefore naturally aged samples are rare and provide scientific reference data beyond regulatory considerations. Tienoxolol was studied after 25 years of storage in the dark under ambient conditions. About 86% of the samples still consisted of tienoxolol and the main impurity (13%) was caused by the hydrolysis of the ester moiety. Protection from humidity is therefore important. Other sensitive groups containing nitrogen and sulfur appear to be quite stable with less than 0.8% conversion over 25 years. In addition, the crystal structure has been solved. Tienoxolol orange needles were found to crystallize in the orthorhombic non-centrosymmetric space group Iba2, indicating that the crystal is a racemic compound. The unit cell parameters at room temperature are a=10.069(5)Å, b=45.831(10)Å, and c=9.822(5)Å and the unit cell volume is 4533(3)Å(3) with Z=8.

01 May 1993·British Journal of PharmacologyQ2 · MEDICINE

Effect of tienoxolol, a new diuretic β‐blocking agent, on urinary prostaglandin excretion in the rat

Q2 · MEDICINE

Article

Author: Alix Cloarec ; François Caussade

The effects of tienoxolol, (ethyl 2‐[3‐[(1,1‐dimethylethyl)amino]‐2‐hydroxypropoxy]‐5‐[(2‐thienylcarbonyl) amino] benzoate, hydrochloride), a novel drug exhibiting both diuretic and β‐adrenoceptor blocking properties, were investigated on urinary 6‐keto‐prostaglandin F1α (6‐keto‐PGF1α) and PGE2 excretion in the rat and compared to those of reference diuretic (furosemide) and β‐adrenoceptor antagonists (acebutolol, propranolol). Since tienoxolol was shown to bind to A1 and A2 adenosine receptors, the action of theophylline was also evaluated.

Tienoxolol (8–128 mg kg−1, p.o.) induced a dose‐related increase of 6‐keto‐PGF1α excretion from 32 mg kg−1 but a significant elevation of urinary PGE2 levels was only reached after administration of 128 mg kg−1. However, renal prostaglandin concentrations were not modified by tienoxolol.

Furosemide (32 mg kg−1) displayed a strong diuretic activity but did not enhance 6‐keto‐PGF1α excretion. Likewise, the latter was unaffected by acebutolol and propranolol (128 mg kg−1) and no significant diuresis was observed following administration of these two β‐blocking agents. Theophylline (64 mg kg−1), like tienoxolol, was able to induce both diuresis and urinary prostaglandin excretion. Furthermore, they bound with similar affinities to A1 and A2 adenosine receptors. This led to the suggestion that a relationship between P1‐purinoceptors, prostaglandin release, diuresis and natriuresis could exist.

Oral co‐administration of NECA (0.2 mg kg−1) with tienoxolol markedly reduced the urinary 6‐keto‐PGF1α excretion observed when tienoxolol was administered alone. However, neither diuresis nor natriuresis were modified, demonstrating that the proposed relationship was untenable.

In conclusion, PGI2 probably does not participate in the diuretic and natriuretic activity of tienoxolol. The increase of urinary 6‐keto‐PGF1α excretion may result not only from the haemodynamic properties of the drug but also from the rise of the urinary flow induced by tienoxolol.

100 Deals associated with Tienoxolol Hydrochloride

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Indication	Highest Phase	Country/Location	Organization	Date
Hypertension	Phase 2	IE	-	-
Hypertension	Phase 2	GB	-	-
Hypertension	Phase 2	FR	UPSA SAS	-
Hypertension	Phase 2	DE	-	-
Hypertension	Phase 2	BE	-	-
Myocardial Ischemia	Phase 2	-	UPSA SAS	-

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