Stereoselective activity of 2-(4-amino-3-chloro-5- trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride to improve the pulmonary function in asthma

Abstract

Abstract. Asthma is a chronic airway disease that is characterized by significantly exacerbated bronchospasms and marked inflammation of the airways. Although the etiology of asthma remains to be determined, genetic predisposition is one of the factors involved. β 2 -agonists compounds may serve as options for the treatment of bronchial asthma. The aim of the present study was to investigate the effects of 2-(4-amino-3-chloro-5-t rifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride (SPFF) and its enantiomers with regard to improving asthmatic pulmonary function and selective binding to β 2 -adrenergic receptor. The bronchoconstrictor action of histamine in guinea pigs was conducted and the results demonstrated that (-)SPFF and (±)SPFF could significantly inhibit the increase of bronchoconstriction induced by histamine, while (+)SPFF did not show an effect. Inflammatory mediator release from allergic lung tissues was determined and it was found that (±)SPFF showed the highest activity among all the tested compounds, while the efficacy of (-)SPFF was similar to that of (+)SPFF. SPFF and its enantiomers stimulated cyclic adenosine monophosphate (cAMP) production in the asthmatic lung tissues examined, showing that asthmatic lung tissues had a significant cAMP enhancement in response to (-)SPFF and (±)SPFF compared with (+)SPFF. Cardiac contractility of the right atria was assessed in the guinea pigs to establish the receptor selectivity of the compounds. The results indicated that all the compounds had high affinities to the β 2 receptor. In conclusion, with regards to asthmatic pulmonary function improvement, (-)SPFF was more efficient as compared to (+) SPFF, while no significant difference was observed for the receptor selectivity of (-)SPFF and (+)SPFF.

Discovery of a Highly Selective β2-Adrenoceptor Agonist with a 2-Amino-2-phenylethanol Scaffold as an Oral Antiasthmatic Agent

“…It has been reported that (−)-trantinterol and (±)-trantinterol similarly relaxed guinea pig airway smooth muscles precontracted by histamine . Moreover, there was no significant difference among (−)-trantinterol, (+)-trantinterol, and (±)-trantinterol in their activities on cAMP accumulation in asthmatic lung tissues . Therefore, we used symmetric synthesis in our study.…”

“…Later, compound 1a was proceeded to a series of clinical testing. , A recent phase III clinical study has shown that trantinterol hydrochloride given 50 μg/d orally twice a day was safe and effective and noninferior to procaterol hydrochloride in the studied population of adult Chinese patients with asthma . However, previous biological studies on compound 1a ,, are either short of a systemic structure–activity relationship study or lack of perspectives on the evaluation of the oral bioavailability of the compound and a comparison with existing selective β 2 -AR agonists on β 2 /β 1 -selectivity.…”

Pharmacology and Therapeutics of Bronchodilators Revisited

“…Nonetheless, trantinterol [SPFF; 2-(4-amino-3chloro-5-trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride] bears a novel scaffold of 2-amino-2phenylethanol instead of the classic scaffold of 2-amino-1-phenylethanol and is an example of a novel b 2 -AR agonist under development (Gan et al, 2003). In guinea pigs, (S)-trantinterol was more effective than (R)trantinterol at causing ASM relaxation, despite the observation that there was no significant difference observed for the receptor selectivity of (S)-trantinterol and (R)-trantinterol (Pan et al, 2014). This finding contrasts with the documentation that other (S)-enantiomers are effectively inert at the b 2 -AR (Jacobson et al, 2018).…”

<p>Ultra Long-Acting β-Agonists in Chronic Obstructive Pulmonary Disease</p>

“… 62 Subsequent in vivo experiments showed that (-) SPFF inhibited histamine-induced bronchoconstriction in guinea pigs while (+) SPFF did not. 63 At the time of this writing, there are no registered clinical trials investigating SPFF.…”